Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0030198 extracellular matrix organization	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Family-signature inference that is correctly constructed and carries independent positive support at family level, but no ADAMTSL1 evidence. Kept, and explicitly not asserted as this gene's demonstrated core function. Reason: Three things give this IEA positive support rather than merely leaving it unrefuted. First, the mapping is careful: IPR013273 (ADAMTS/ADAMTS-like) is the only one of ADAMTSL1's fourteen InterPro entries with any GO mapping, and it maps to GO:0030198 alone - no peptidase, protease or hydrolase term - even though the signature also matches the catalytic ADAMTS metalloproteases. Second, GO:0030198 does not depend on the domain ADAMTSL1 lacks: catalytic family members reach the term through proteolysis, but ADAMTSL2, ADAMTSL4 and THSD4 reach it non-catalytically through fibrillin microfibril assembly, so the term sits at the level of generality at which a mechanistically heterogeneous family genuinely agrees, and a non-catalytic route to it is available to this architecture in principle. This ground has to be qualified for ADAMTSL1 in particular, and the qualification is a measured negative rather than an absence: in the one experiment that tested it, recombinant human ADAMTSL-1 did not bind the N-terminal half of fibrillin-1 in the same SPR panel in which ADAMTSL-2, ADAMTSL-3 and papilin did - and the same experiments report the C-terminal half negative for every ADAMTSL tested, albeit as data not shown, so the exclusion covers fibrillin-1 entire - and it did not bind the non-catalytic region of ADAMTS-10 either. Only the fibrillin-1 half of that is discriminating, and the two must not be double-counted: ADAMTSL-2 is equally negative against ADAMTS-10 and still reaches GO:0030198, ADAMTS-10 binding was shown only for ADAMTSL-3, and THSD4 was never tested against it. The load-bearing result is the fibrillin-1 negative alone, and it is sufficient: the specific route by which the relatives reach this term is excluded for ADAMTSL1. That does not refute GO:0030198, which is far broader than fibrillin-1 binding, but it removes the strongest mechanistic analogy and it is a further reason the term cannot be treated as core here. Third, PAINT arrived at the same term independently: GO:0030198 is an IBD annotation at PTN000347317, seeded by fourteen gene sources (eleven mouse, two fly, one nematode), and that node sits above ADAMTSL1. That last step is what makes this ground bear on the gene rather than merely on its family, so it is worth stating how it is established: mouse Adamtsl1 is in PANTHER subfamily SF157, the same subfamily as human ADAMTSL1, and it receives the GO:0031012 IBA from PTN000347317, so that node is an ancestor of SF157 and therefore of ADAMTSL1. All three are family-level, and that is the limit of the case. What the annotation does not have is any ADAMTSL1 evidence. The laboratory that discovered the protein states that its tissue function is unknown and that matrix assembly and turnover is an expectation drawn from relatives; being resident in the matrix and being an MMP10 substrate places ADAMTSL1 within matrix remodelling but does not show that it organises the matrix. Hence KEEP_AS_NON_CORE rather than ACCEPT, since ACCEPT would assert this as the gene's core function and the evidence does not reach that. Not MARK_AS_OVER_ANNOTATED either, on the three grounds above. The concurrent ADAMTSL5 review marks its identical InterPro IEA MARK_AS_OVER_ANNOTATED; the two genes are in the same IBA position for this term, because neither receives the GO:0030198 IBA from PTN000347317 that ADAMTSL2, ADAMTSL4 and THSD4 do (computed in the bioinformatics census, section 1). They are no longer in the same evidentiary position overall, and the difference now runs against this review rather than for it: ADAMTSL5 has its own IDA to GO:0031012 plus microfibril and heparin binding, while ADAMTSL1 has a measured negative against the very route by which the family reaches GO:0030198, so the better-supported gene is the one taking the harsher action. That is an argument for settling the line family-wide rather than a reason to change one gene in isolation, so it is carried into suggested_questions rather than resolved here. Supporting Evidence: PMID:28722276 The function of punctin-1 in tissues is currently unknown, however, by analogy with other family members (Apte 2009; Dubail and Apte 2015; Hubmacher and Apte 2015), there is a strong possibility that it mediates the assembly and turnover of extracellular matrix at the affected sites. PMID:24281761 we identified the extracellular matrix protein ADAMTS-like protein 1 (ADAMTSL1) as a direct MMP10 substrate file:human/ADAMTSL1/ADAMTSL1-bioinformatics/RESULTS.md Entries with a CATALYTIC ACTIVITY comment: none. file:human/ADAMTSL1/ADAMTSL1-deep-research-affinage.md Direct biochemical demonstration of an enzymatic activity for the mammalian protein has not been established in the available corpus. file:interpro/panther/PTHR13723/PTHR13723-paint.tsv PTHR13723 PTN000347317 GO:0030198 P IBD false PMID:22242013 ADAMTSL-2, -3, and papilin polypeptides interacted with the N-terminal half of fibrillin-1, while ADAMTSL-1 did not. Knowledge gap: Whether ADAMTSL1 itself participates in organising the extracellular matrix, as opposed to merely residing in it and being turned over within it, has never been tested. OPEN BIOLOGY BP_DARK Resolve: A microfibril or matrix-assembly assay using recombinant full-length ADAMTSL1, together with matrix phenotyping of an Adamtsl1-null mouse, would settle it. Both have been blocked in practice by the absence of a full-length expression construct. "The function of punctin-1 in tissues is currently unknown, however, by analogy with other family members (Apte 2009; Dubail and Apte 2015; Hubmacher and Apte 2015), there is a strong possibility that it mediates the assembly and turnover of extracellular matrix at the affected sites." — PMID:28722276 "A plasmid construct for full-length ADAMTSL1 is presently unavailable." — PMID:28722276 "ADAMTSL-2, -3, and papilin polypeptides interacted with the N-terminal half of fibrillin-1, while ADAMTSL-1 did not." — PMID:22242013
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-5173005	KEEP AS NON CORE	Summary: True but non-core. ADAMTSL1's thrombospondin repeats really are glucosylated by B3GLCT in the ER lumen, so the protein occupies that compartment during biosynthesis; it acts in the extracellular matrix. Reason: The underlying biology is experimentally supported for this gene rather than inferred from pathway membership alone: mass spectrometry of punctin-1 detected the fucose-glucose disaccharide that B3GLCT produces on TSR2, TSR3 and TSR4, and mutating the modified residues reduces secretion. The compartment assignment is therefore correct. It is marked non-core because the endoplasmic reticulum lumen is a biosynthetic transit compartment for a secreted protein, not its site of action, and because the Reactome pipeline projects the compartment of a reaction's participant set: this reference annotates about nine gene products with the same three terms, so it is one statement about set membership rather than an observation about ADAMTSL1. Supporting Evidence: PMID:17395588 Mutation of the putative modified Ser/Thr residues in TSR2, TSR3, and TSR4 led to significantly decreased levels of secreted punctin-1.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-5173192	KEEP AS NON CORE	Summary: Same statement as the B3GLCT row, from the upstream reaction of the same pathway. POFUT2 acts on ADAMTSL1's thrombospondin repeats in the ER lumen; kept as a transit location rather than a functional one. Reason: POFUT2 is the ER-resident enzyme that installs the O-fucose on which B3GLCT builds, and ADAMTSL1 is a demonstrated substrate: the O-fucose was mapped to Thr48, Thr312, Ser391 and Thr451 by mass spectrometry, and C-mannosylation of the adjacent tryptophans in the same repeat was mapped in the companion study, with both modifications acting together as a gate on export. The compartment is correct and better supported than the other two rows, but it remains a biosynthetic transit compartment rather than the site where the protein functions. This is one of three GOA rows asserting the identical term for the same gene from three reactions of one Reactome pathway. Supporting Evidence: PMID:19671700 Together, these modifications appear to provide a quality control mechanism for punctin-1 secretion. PMID:17395588 the data define a critical role for N-glycosylation and O-fucosylation in the biosynthesis of punctin-1
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-6785565	KEEP AS NON CORE	Summary: The weakest of the three identical rows: it derives from a Reactome FailedReaction modelling the Peters-plus disease state, in which the B3GALTL G393E variant does not glucosylate its substrates. The location it asserts is still correct, but it carries no information the two working reactions do not already supply. Reason: Verified against the Reactome content service: R-HSA-6785565 has schemaClass FailedReaction, its catalyst is the B3GALTL G393E disease variant, and it has inputs but no outputs. The GO pipeline emits the compartment of the input participant set regardless of whether the reaction proceeds, so ADAMTSL1 receives the same endoplasmic reticulum lumen assignment it already has from R-HSA-5173005. Kept because the compartment claim is not wrong and ADAMTSL1 is a genuine B3GLCT substrate, but marked non-core on the same transit-compartment grounds as its two siblings, and flagged as redundant. Whether a FailedReaction should emit a location annotation identical to that of the corresponding working reaction is raised as a question for the Reactome-GO pipeline rather than treated as a defect in this gene's record. Supporting Evidence: PMID:17395588 Mutation of the putative modified Ser/Thr residues in TSR2, TSR3, and TSR4 led to significantly decreased levels of secreted punctin-1.
GO:0031012 extracellular matrix	IDA Q8N6G6-1 PMID:11805097 Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extrace...	NEW	Summary: Proposed new annotation. ADAMTSL1 is the only one of the 26 human members of PANTHER family PTHR13723 with no extracellular matrix annotation of any kind, even though its matrix deposition is directly observed in human cells, endogenous untagged protein is recovered from human fibroblast secretomes (PMID:24281761), and its mouse orthologue receives the term by IBA from the same PANTHER node. Reason: The gap was found by census rather than by inspection. PAINT holds GO:0031012 as an IBD annotation at node PTN000347317; 24 of the 26 human members of PTHR13723 receive it by IBA from that node, and the one further exception, PAPLN, holds the term from its own evidence, which is the expected behaviour since PAINT does not lay an IBA over a direct annotation. ADAMTSL1 has neither. The gap is species-specific rather than subfamily-specific: mouse Adamtsl1 (Q8BLI0), the same PANTHER subfamily SF157, does receive the IBA from PTN000347317 and additionally carries three HDA rows from matrisome proteomics. Human evidence is not lacking. UniProt records the location as supported by three experimental references, the founding paper shows recombinant punctin deposited punctately into the cell substratum and excluded from focal contacts, and endogenous untagged ADAMTSL1 was recovered from human fibroblast secretomes and named as a direct MMP10 substrate. The caveat on the primary evidence is that the 2002 assay used epitope-tagged protein in a heterologous cell line, which is why the secretome result is cited alongside it: it is native protein in a primary human cell type, and it is independent of the tag. The isoform field records that the assayed material was the 525-residue punctin-1 form, which is what was purified and expressed; it is not a claim that the localisation is restricted to that isoform, and it should not be read as one. Isoforms 1 to 4 all retain the signal peptide, so all are expected to be secreted, while isoforms 5 and 6 delete it and would not be. Supporting Evidence: PMID:11805097 In transfected COS-1 cells, punctin is deposited in the cell substratum in a punctate fashion and is excluded from focal contacts. PMID:24281761 we identified the extracellular matrix protein ADAMTS-like protein 1 (ADAMTSL1) as a direct MMP10 substrate file:human/ADAMTSL1/ADAMTSL1-bioinformatics/RESULTS.md Members with no `GO:0031012` annotation of any kind: ADAMTSL1. file:interpro/panther/PTHR13723/PTHR13723-paint.tsv PTHR13723 PTN000347317 GO:0031012 C IBD false

Core Functions

A secreted, heavily glycosylated ADAMTS-like protein deposited into the pericellular matrix. The location is the only part of this that the gene's own data establishes, so it is the only structured claim made here. No molecular function, ligand or binding partner has been identified, so no molecular-function term is asserted; and although the gene carries GO:0030198 extracellular matrix organization from the family InterPro signature, that term has no ADAMTSL1-specific support, so it is deliberately not repeated as a core process here and is instead reviewed on its own row as KEEP_AS_NON_CORE, where its family- level basis and the limits of that basis are set out. What can be said positively about the protein's role in matrix remodelling is negative in form: it is a substrate of extracellular proteolysis rather than an agent of it, having none of the catalytic machinery of the ADAMTS proteases and being itself cleaved by MMP10 in fibroblast secretomes.

Cellular Locations:

extracellular matrix

Supporting Evidence:

PMID:11805097
In transfected COS-1 cells, punctin is deposited in the cell substratum in a punctate fashion and is excluded from focal contacts.
PMID:24281761
we identified the extracellular matrix protein ADAMTS-like protein 1 (ADAMTSL1) as a direct MMP10 substrate
PMID:28722276
it also contains a family of seven ADAMTS-like proteins (ADAMTSL family) comprising an ADAMTS ancillary domain but lacking the protease domain and thus, enzymatic activity

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

The only InterPro entry matched by ADAMTSL1 that carries a GO mapping is IPR013273 (ADAMTS/ADAMTS-like), and it maps to GO:0030198 extracellular matrix organization alone. Although the signature spans the catalytic ADAMTS metalloproteases, the mapping does not include any peptidase or hydrolase term, so no catalytic activity is propagated to the non-catalytic members of the family through this route.

Reactome:R-HSA-5173005

B3GALTL transfers glucose to O-fucosyl-proteins

Reaction of the O-glycosylation of TSR domain-containing proteins pathway in which B3GLCT, an ER membrane enzyme, adds glucose to the O-fucose already present on thrombospondin type-1 repeats. ADAMTSL1 is a member of the O-fuc-proteins participant set, which Reactome places in the endoplasmic reticulum lumen.

Reactome:R-HSA-5173192

POFUT2 transfers fucose to TSR domain-containing proteins

Reaction in which the ER-resident enzyme POFUT2 attaches fucose to the conserved Ser or Thr of thrombospondin type-1 repeats. ADAMTSL1 is a member of the POFUT2 substrates participant set, placed by Reactome in the endoplasmic reticulum lumen.

Reactome:R-HSA-6785565

Defective B3GALTL does not transfer glucose to O-fucosyl-proteins

A Reactome FailedReaction modelling the Peters-plus syndrome disease state, in which the B3GALTL G393E variant fails to glucosylate O-fucosylated thrombospondin repeats. ADAMTSL1 appears as an input to a reaction that by construction does not proceed, yet the GO pipeline emits the same endoplasmic reticulum lumen location as for the working reaction.

PMID:11805097

Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extracellular matrix.

Punctin/ADAMTSL-1 is a secreted glycoprotein resembling the ADAMTS proteases but lacking the pro-metalloprotease and disintegrin-like domains, and containing four thrombospondin type-1 repeats in the short form that was purified.

"Punctin lacks the pro-metalloprotease and the disintegrin-like domain typical of this family but contains other ADAMTS domains in precise order including four thrombospondin type I repeats."
Recombinant punctin expressed in transfected COS-1 cells is deposited into the cell substratum in a punctate pattern and is excluded from focal contacts. This is the observation that gave the protein its name and the primary human evidence that it reaches the extracellular matrix.

"In transfected COS-1 cells, punctin is deposited in the cell substratum in a punctate fashion and is excluded from focal contacts."
The gene is expressed in adult skeletal muscle, and the authors present punctin as the founding member of the ADAMTS-like family whose matrix function was at that point prospective rather than demonstrated.

"Punctin is the first member of a novel family of ADAMTS-like proteins that may have important functions in the extracellular matrix."

PMID:17395588

O-fucosylation of thrombospondin type 1 repeats in ADAMTS-like-1/punctin-1 regulates secretion: implications for the ADAMTS superfamily.

The thrombospondin repeats of punctin-1 carry POFUT2-type O-fucose, extended in TSR2, TSR3 and TSR4 to a fucose-glucose disaccharide, and mutating the modified Ser/Thr residues reduces the amount of protein secreted. This is the experimental basis for ADAMTSL1's participation in the two Reactome ER-lumen glycosylation reactions.

"Mutation of the putative modified Ser/Thr residues in TSR2, TSR3, and TSR4 led to significantly decreased levels of secreted punctin-1."
N-glycosylation and O-fucosylation together are required for efficient biosynthesis of the protein.

"the data define a critical role for N-glycosylation and O-fucosylation in the biosynthesis of punctin-1"

PMID:19671700

Post-translational modification of thrombospondin type-1 repeats in ADAMTS-like 1/punctin-1 by C-mannosylation of tryptophan.

Trp39 and Trp42 of the first thrombospondin repeat carry C-linked mannose, adjacent to the O-fucose site, and substituting these tryptophans changes secretion efficiency. The authors conclude that the two modifications together act as a quality-control mechanism on export.

"Together, these modifications appear to provide a quality control mechanism for punctin-1 secretion."
Mass spectrometry of recombinant human punctin-1 identified the TSR1 peptide spanning residues 36-49 bearing two mannose residues and a Glc-Fuc disaccharide.

"Analysis of tryptic fragments of recombinant human punctin-1 by mass spectrometry identified a peptide derived from TSR1 containing the (36)WDAWGPWSECSRTC(49) sequence of interest modified with two mannose residues and a Glc-Fuc disaccharide (O-fucosylation)."

PMID:24281761

Time-resolved analysis of the matrix metalloproteinase 10 substrate degradome.

Endogenous ADAMTSL1 was identified in human fibroblast secretomes by terminal amine isotopic labelling of substrates and shown to be a direct MMP10 substrate. This places native, untagged ADAMTSL1 in the extracellular compartment of a primary human cell type and shows it is subject to extracellular proteolysis rather than performing it.

"we identified the extracellular matrix protein ADAMTS-like protein 1 (ADAMTSL1) as a direct MMP10 substrate"

PMID:28722276

Identification and functional analysis of an ADAMTSL1 variant associated with a complex phenotype including congenital glaucoma, craniofacial, and other systemic features in a three-generation human pedigree.

The ADAMTS-like proteins are defined as comprising the ADAMTS ancillary domains while lacking the protease domain, and therefore lacking enzymatic activity.

"it also contains a family of seven ADAMTS-like proteins (ADAMTSL family) comprising an ADAMTS ancillary domain but lacking the protease domain and thus, enzymatic activity"
Full-length ADAMTSL1 has thirteen thrombospondin type-1 repeats, four Ig-like C2-type domains and one PLAC domain over 1762 residues, and punctin-1 is the 525-residue short splice variant with four repeats.

"Despite being the prototypic ADAMTSL, little is currently known about ADAMTSL1, which contains thirteen thrombospondin type 1 repeats (TSRs), four Immunoglobulin-like C2-type domains and a single PLAC (protease and lacunin) domain in its full-length form (1762 amino acids) and four TSRs in a short splice variant named punctin-1 (525 amino acids)"
The group that discovered the protein states that its tissue function is unknown and that a role in matrix assembly and turnover is an expectation drawn from other family members rather than an ADAMTSL1 result.

"The function of punctin-1 in tissues is currently unknown, however, by analogy with other family members (Apte 2009; Dubail and Apte 2015; Hubmacher and Apte 2015), there is a strong possibility that it mediates the assembly and turnover of extracellular matrix at the affected sites."
A heterozygous p.Trp42Arg allele at a C-mannosylation site cosegregates with a multisystem phenotype; the mutant protein is retained intracellularly and also reduces secretion of cotransfected wild-type protein.

"p.Trp42Arg punctin-1 was not secreted and accumulated in cells and 2) in the presence of the mutant construct, wild-type punctin-1 was secreted at reduced levels and also accumulated intracellularly"
All of the functional work was done on the short punctin-1 form because no full-length expression construct existed, which is why the experimental coverage of this gene is confined to isoform Q8N6G6-1.

"A plasmid construct for full-length ADAMTSL1 is presently unavailable."

PMID:22014523

MADD-4 is a secreted cue required for midline-oriented guidance in Caenorhabditis elegans.

MADD-4, the C. elegans protein most closely related to ADAMTSL1 and ADAMTSL3, is a secreted guidance cue acting through the netrin receptor UNC-40/DCC. The authors explicitly decline to extend a biological role to the mammalian orthologues.

"The biological role of MADD-4 orthologs, including ADAMTSL1 and 3 in mammals, is unknown."

PMID:30714143

ADAMTSL1 and mandibular prognathism.

Two rare ADAMTSL1 missense variants segregate with mandibular prognathism in Thai families, and mouse Adamtsl1 is expressed in the condensed mesenchyme of the condyle but not in long-bone cartilage. The mechanism the authors propose requires ADAMTSL1 to cleave aggrecan, an activity the protein's domain content does not support, and they label it a hypothesis.

"We hypothesize that mutations in ADAMTSL1 cause failure to cleave aggrecan in the condylar cartilage, and that leads to overgrowth of the mandible."

PMID:35115729

Disentangling glial diversity in peripheral nerves at single-nuclei resolution.

Adamtsl1 is used as one of three transcriptional markers defining a myelinating Schwann cell subtype in mouse peripheral nerve that preferentially ensheathes motor axons. The gene's own function is not assayed.

"including a subtype characterized by expression of Pmp2, Adamtsl1 and Cldn14 that preferentially myelinates motor axons"

PMID:22242013

Microenvironmental regulation by fibrillin-1.

Surface plasmon resonance with recombinant human ADAMTSL-1, -2 and -3 against the N-terminal half of fibrillin-1 found that ADAMTSL-2 and -3 bound and ADAMTSL-1 did not. This is a direct, measured negative for ADAMTSL1 against the partner through which the other ADAMTS-like proteins reach the extracellular matrix organization term.

"ADAMTSL-2, -3, and papilin polypeptides interacted with the N-terminal half of fibrillin-1, while ADAMTSL-1 did not."
The negative covers fibrillin-1 in its entirety, not only the N-terminal half: binding to the C-terminal half was negative for every ADAMTSL protein in the panel. Held to a lower evidentiary standard than the N-terminal result, though: it is reported as data not shown, with no figure or table behind it, whereas the N-terminal negative is reported as an outcome of a panel that is displayed - Figure 5a shows sensorgrams for the binders only, so the paper contains no ADAMTSL-1 trace for either half.

"Binding to the C-terminal half of fibrillin-1 was negative for all ADAMTSL proteins tested"
In the same study ADAMTSL-1 also failed to bind the non-catalytic C-terminal region of ADAMTS-10, which ADAMTSL-3 binds with high affinity. This result is corroborating rather than discriminating and must not be added to the fibrillin-1 one: ADAMTSL-2 is equally negative against ADAMTS-10 and still reaches GO:0030198, ADAMTS-10 binding was shown only for ADAMTSL-3, and ADAMTSL-6/THSD4 was never tested against it, so ADAMTS-10 is not what places ADAMTSL-2 or -6 in the fibrillin-1 pathway. The discriminating result is the fibrillin-1 negative alone.

"However, neither ADAMTSL-2 nor -1 bound to ADAMTS-10, indicating that ADAMTS enzymes may partner only with specific ADAMTSL proteins."

PMID:24634412

Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth.

ADAMTSL1 was identified as a Hedgehog-responsive gene in primary chondrosarcoma xenografts treated with the SMO inhibitor IPI-926, and manipulating it altered chondrosarcoma cell proliferation. This is the only gene-specific functional perturbation result reported for ADAMTSL1, and Apte is a co-author.

"Gene profiling studies identified genes differentially expressed in chondrosarcomas following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell proliferation."

PMID:39880678

Pmp2+ Schwann Cells Maintain the Survival of Large-Caliber Motor Axons.

Ablating the Schwann cell population co-marked by Adamtsl1, Cldn14 and Pmp2 causes loss of large-caliber motor axons. The perturbation is of the cell population, not of the gene, so the phenotype is a property of the cell type.

"Recently, we identified a population of Schwann cells (SCs) expressing Adamtsl1 , Cldn14 , and Pmp2 (a.k.a. PMP2+ SCs) that preferentially myelinate large-caliber motor axons."

file:human/ADAMTSL1/ADAMTSL1-uniprot.txt

UniProtKB Q8N6G6 (ATL1_HUMAN) ADAMTS-like protein 1 record

The feature table over the 1762-residue precursor lists a signal peptide, nine annotated thrombospondin type-1 repeats, four Ig-like C2-type domains and a PLAC domain, with no metalloprotease domain, no disintegrin-like domain, no prodomain and no zinc-binding site. The entry states the absence explicitly and records no catalytic activity and no EC number.

"lacks the metalloprotease and disintegrin-like domains which are"
Despite that, the entry carries the molecular-function keyword Hydrolase (KW-0378), which is what generates the GO:0016787 hydrolase activity cross-reference in the entry's own GO list. This annotation is not present in GOA, because keyword-derived annotations were withdrawn for cellular organisms.

"Extracellular matrix; Glycoprotein; Hydrolase; Immunoglobulin domain;"
The keyword-derived hydrolase activity term appears in the entry's own GO cross-reference block with evidence IEA:UniProtKB-KW.

"GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW."
The entry records that PAN-GO assigns no annotations to this protein from evolutionary models, consistent with the complete absence of IBA rows in GOA.

"PAN-GO; Q8N6G6; 0 GO annotations based on evolutionary models."
The ADAMTS spacer region named in the description is called by Pfam and InterPro rather than by a UniProt FT DOMAIN line, which is why it does not appear in the feature-table enumeration above.

"Pfam; PF05986; ADAMTS_spacer1; 1."
Tissue expression is highest in adult skeletal muscle.

"Expressed primarily in adult skeletal muscle."

file:human/ADAMTSL1/ADAMTSL1-bioinformatics/RESULTS.md

PTHR13723 annotation census for ADAMTSL1

Of the 26 human members of PANTHER family PTHR13723, 24 receive GO:0031012 extracellular matrix by IBA from node PTN000347317. PAPLN does not, but holds the term from its own evidence. ADAMTSL1 is the only human member of the family with no GO:0031012 annotation from any evidence code, while its mouse orthologue - same subfamily SF157 - does receive the IBA from the same node.

"**Members with no `GO:0031012` annotation of any kind: ADAMTSL1.**"
Within the ADAMTS-like branch, ADAMTSL1 and THSD4 carry the Hydrolase keyword while ADAMTSL2, ADAMTSL3, ADAMTSL4 and ADAMTSL5 do not, and none of the six has a catalytic activity comment.

"Entries with a CATALYTIC ACTIVITY comment: none."
PAINT records IKR and IRD loss calls at node PTN002673039 that block metalloendopeptidase activity and proteolysis from propagating down the ADAMTS-like branch, but in GOA the loss reaches only ADAMTSL2. ADAMTSL1 receives neither the catalytic terms nor the negation.

"So the loss call is recorded for part of the branch and simply absent for the rest - ADAMTSL1 inherits neither the catalytic terms nor the statement that they do not apply."

file:interpro/panther/PTHR13723/PTHR13723-paint.tsv

PANTHER PTHR13723 PAINT node annotations

PAINT records an inferred-from-key-residues loss of metalloendopeptidase activity at node PTN002673039, negating the term that the family node PTN000347317 carries. A companion inferred-from-rapid-divergence row does the same for proteolysis.

"PTHR13723 PTN002673039 GO:0004222 F IKR true PANTHER:PTN000347317"
The family node PTN000347317 carries GO:0031012 extracellular matrix as an IBD annotation, which is the source of the IBA rows that 24 of 26 human family members receive and ADAMTSL1 does not.

"PTHR13723 PTN000347317 GO:0031012 C IBD false"

file:human/ADAMTSL1/ADAMTSL1-deep-research-affinage.md

Affinage mechanistic annotation for ADAMTSL1 (human)

The provider record passed its own gates (gates_passed True, faith 100 percent, ten numeric PMIDs, no preprint identifiers in PMID-shaped fields) and its central framing - a secreted matrix glycoprotein without the catalytic domains, with no demonstrated enzymatic activity - agrees with UniProt and with the primary literature.

"Direct biochemical demonstration of an enzymatic activity for the mammalian protein has not been established in the available corpus."

Suggested Experiments

Experiment: Build a full-length ADAMTSL1 expression construct and purify the 1762-residue protein. This is the rate-limiting step for everything else: the 2017 study states that no such construct existed, so every published biochemical result is confined to the 525-residue punctin-1 splice form.

Hypothesis: The nine thrombospondin repeats, four immunoglobulin-like domains and PLAC domain that are absent from punctin-1 carry functions that no published experiment has been able to test.

Type: recombinant protein expression

Experiment: An unbiased partner search rather than another candidate test: pull-down or proximity- labelling from a matrix-producing human cell line using recombinant full-length ADAMTSL1 as bait, with mass-spectrometric identification. Candidate SPR should be reserved for fibrillin-2 and heparin, which are not reported as tested anywhere, and for LTBP1 and LTBP4, whose ADAMTSL1 results are absent from that study's main text but may sit in a supplementary table not present in the cached record and are worth checking before assaying. Use ADAMTSL2 or ADAMTSL3 as the positive control. Fibrillin-1 and the non- catalytic region of ADAMTS-10 should be included only as controls, since recombinant human ADAMTSL-1 has already been shown not to bind either, and repeating them with the 1762-residue isoform would additionally test whether that published negative extends to the long form.

Hypothesis: ADAMTSL1 has a matrix binding partner outside the fibrillin-1 / ADAMTS-10 axis that unites the rest of the ADAMTS-like family.

Type: protein-protein interaction assay

Experiment: Assay fibrillin microfibril deposition in fibroblast cultures with ADAMTSL1 knocked down or supplemented with recombinant protein, the standard test used to establish the matrix-organising role of the other ADAMTS-like proteins.

Hypothesis: ADAMTSL1 promotes or restrains fibrillin microfibril deposition, which would make GO:0030198 a gene-specific rather than a family-level annotation.

Type: cell-based matrix assembly assay

Experiment: Phenotype an Adamtsl1-null mouse for the tissues where the human phenotype localises - ocular anterior segment and intraocular pressure, mandibular condylar cartilage, dentition, and skeletal muscle - and compare the peripheral-nerve phenotype directly with that of Pmp2-positive Schwann cell ablation.

Hypothesis: The peripheral-nerve phenotype attributed to Pmp2-positive Schwann cells is a property of that cell population rather than of Adamtsl1, which is only one of its markers.

Type: mouse knockout phenotyping

Experiment: Map the MMP10 cleavage site in ADAMTSL1 and test whether the released fragment has activity of its own, since a matrix protein whose only reported enzymatic relationship is being a substrate may be functioning through a processed form.

Hypothesis: ADAMTSL1 acts through an MMP10-generated fragment rather than as an intact protein.

Type: degradomics and fragment activity assay

Experiment: Localise endogenous ADAMTSL1 protein, not transcript, in adult human skeletal muscle and in the ocular anterior segment. All existing localisation data come from recombinant protein in transfected cells or from secretome proteomics, so an antibody-based localisation in the affected tissues would put the extracellular matrix annotation on native protein in its own tissue context.

Hypothesis: Native ADAMTSL1 occupies the extracellular matrix of the tissues where its loss produces disease, not only that of transfected cells in culture.

Type: immunohistochemistry

Knowledge Gaps

What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).

Gap: No molecular function is known for ADAMTSL1: no ligand, no binding partner, no activity and no structural role has been demonstrated, and the gene carries no molecular-function annotation of any evidence code in GOA.

OPEN BIOLOGY MF_DARK

What is known: Well established: the protein's domain content (thrombospondin type-1 repeats, four Ig- like C2-type domains, ADAMTS spacer, PLAC domain, no catalytic domains), its secretion and matrix deposition, the glycosylation chemistry that gates its export, its cleavage by MMP10, and a dominant-negative human allele. Also now bounded on the other side by measured negatives rather than by silence: recombinant human ADAMTSL-1 did not bind the N-terminal half of fibrillin-1 in an SPR panel where ADAMTSL-2, ADAMTSL-3 and papilin did, and the same experiments report the C-terminal half negative for every ADAMTSL tested, which is what licenses stating the exclusion as fibrillin-1 binding rather than N-terminal fibrillin-1 binding, though that second half is given as data not shown. ADAMTSL-1 also did not bind the non-catalytic region of ADAMTS-10. Only the fibrillin-1 result discriminates ADAMTSL1 from its relatives - ADAMTSL-2 is equally negative against ADAMTS-10 and ADAMTSL-6/THSD4 was never tested against it - so what is excluded is fibrillin-1 binding, with the ADAMTS-10 result corroborating rather than adding to it, and both subject to the caveat that the construct's isoform is not stated. Entirely open: what the protein does bind, and what it does once it is in the matrix.

Significance: ADAMTSL1 is the prototype of the ADAMTS-like family and is implicated in a multisystem developmental disorder, yet has no molecular handle at all. Until a partner is identified the disease mechanism cannot be modelled beyond loss of secretion, and the family-level extracellular matrix organization inference cannot be made specific.

What would resolve it: Identification of a physical binding partner for recombinant full-length ADAMTSL1 would supply the first molecular-function term. The obvious family candidates are now poorer candidates than they look: fibrillin-1 and ADAMTS-10 were both tested by SPR in PMID:22242013 and both were negative, so an unbiased search is more appropriate than another fibrillin-1 experiment. Fibrillin-2 is not reported as tested anywhere, and FBN2 appears among the affinity-purification hits, so it is the one family-shaped hypothesis still standing. No LTBP result for ADAMTSL1 appears in the main text of PMID:22242013 either, but LTBP-1 and LTBP-4 were coupled to chips in the same experiments and the LTBP data sit in a supplementary table absent from the cached record, so untested is not a safe reading for those. Producing a construct for the 1762-residue form is the prerequisite for all of it, and would also determine whether the published negatives extend to the long isoform.

Provenance (the field's own admissions):

"The function of punctin-1 in tissues is currently unknown, however, by analogy with other family members (Apte 2009; Dubail and Apte 2015; Hubmacher and Apte 2015), there is a strong possibility that it mediates the assembly and turnover of extracellular matrix at the affected sites." — PMID:28722276
"The biological role of MADD-4 orthologs, including ADAMTSL1 and 3 in mammals, is unknown." — PMID:22014523
"However, neither ADAMTSL-2 nor -1 bound to ADAMTS-10, indicating that ADAMTS enzymes may partner only with specific ADAMTSL proteins." — PMID:22242013

Deep Research

Affinage

(ADAMTSL1-deep-research-affinage.md)

Affinage mechanistic annotation for ADAMTSL1 (human) Affinage Affinage (Claude Sonnet reading pass + Opus synthesis pass) 10 citations

Affinage mechanistic annotation for ADAMTSL1 (human)

Current model (mechanistic narrative)

ADAMTSL1 (punctin) is a secreted, hatchet-shaped extracellular matrix glycoprotein built from four thrombospondin type I repeats but lacking the metalloprotease and disintegrin-like domains of catalytic ADAMTS family members, and it is deposited in a punctate pattern into the cell substratum PMID:11805097. Its secretion is governed by post-translational modification: C-mannosylation of Trp42 within a W-x-x-W motif is required for proper folding and export, and the disease-associated p.Trp42Arg substitution abolishes secretion, causing intracellular retention and a dominant-negative reduction in secretion of co-expressed wild-type protein PMID:28722276. Its thrombospondin repeats additionally carry the glucose-β1,3-fucose disaccharide added by B3GLCT PMID:18720094, and the mature protein is a direct proteolytic substrate of MMP10 PMID:24281761, placing ADAMTSL1 within a regulated ECM remodeling context. Functionally, the C. elegans ortholog MADD-4 acts as a secreted UNC-40/DCC-dependent midline guidance cue, implicating the family in nervous system patterning PMID:22014523, while in mammals ADAMTSL1 marks a Pmp2+ myelinating Schwann cell subtype that ensheathes large-caliber motor axons PMID:35115729. ADAMTSL1 expression is also responsive to Hedgehog signaling and modulates chondrosarcoma proliferation PMID:24634412. Direct biochemical demonstration of an enzymatic activity for the mammalian protein has not been established in the available corpus.

Affinage mechanism profile (its own GO/Reactome grounding)

Recorded for reference. The AIGR evaluation found this grounding is coarse (collapses to general parents) and can contradict the narrative — do not import these GO ids directly; re-ground from the narrative + PMIDs.

molecular_activity: (none)
localization: GO:0005576 extracellular region, GO:0031012 extracellular matrix
pathway (Reactome): (none)
partners: B3GLCT, MMP10
complexes: (none)

Dated findings (citation-anchored)

Year	Confidence	Finding	PMIDs	Journal
2002	High	ADAMTSL1 (punctin) is a secreted glycoprotein that lacks the pro-metalloprotease and disintegrin-like domains of ADAMTS proteases but contains four thrombospondin type I repeats. It is processed by signal peptidase (N-terminus: EEDRD), contains a single N-linked glycosylation site, harbors disulfide bonds, and adopts a hatchet-shaped conformation with a globular region and short stem as shown by rotary shadowing. In transfected COS-1 cells, it is deposited in the cell substratum in a punctate fashion and excluded from focal contacts.	PMID:11805097	The Journal of biological chemistry
2009	Medium	ADAMTSL1 carries the rare glucose-β1,3-fucose disaccharide modification on its thrombospondin type I repeats (TSRs), placed there by the β1,3-glucosyltransferase B3GLCT. This O-linked fucose modification on TSR-containing proteins is disrupted in Peters'-plus syndrome.	PMID:18720094	Annals of medicine
2013	Medium	ADAMTSL1 is a direct substrate of matrix metalloproteinase 10 (MMP10); MMP10 cleaves ADAMTSL1 in fibroblast secretomes as identified by time-resolved terminal amine isotopic labeling of substrates (TAILS) degradomics.	PMID:24281761	Molecular & cellular proteomics : MCP
2014	Medium	ADAMTSL1 regulates chondrosarcoma cell proliferation downstream of Hedgehog (Hh) pathway signaling; ADAMTSL1 expression is reduced by the SMO inhibitor IPI-926, and manipulation of ADAMTSL1 levels affects chondrosarcoma neoplastic proliferation.	PMID:24634412	Molecular cancer therapeutics
2017	High	A heterozygous missense mutation p.Trp42Arg in ADAMTSL1 abolishes secretion of the protein; the mutant protein is retained intracellularly and exerts a dominant-negative effect by reducing secretion of co-transfected wild-type ADAMTSL1. Trp42 is the site of C-mannosylation, implicating this modification as necessary for proper ADAMTSL1 folding/secretion.	PMID:28722276	Human mutation
2021	Medium	C-mannosylation of the first Trp in the W-x-x-W/C motif of ADAMTSL1 (at Trp42) is critical for protein folding, sorting, and secretion; a disease-associated variant disrupting this motif (p.Trp42Arg) confirms the functional importance of this modification in vivo.	PMID:34500691	Molecules (Basel, Switzerland)
2011	Medium	The C. elegans ortholog MADD-4 (most closely related to mammalian ADAMTSL1 and ADAMTSL3) is a secreted guidance cue from dorsal and ventral nerve cords that attracts sensory axons and muscle arms; its activity requires the netrin receptor UNC-40/DCC acting cell-autonomously. This establishes a guidance function for the ADAMTSL family in nervous system patterning.	PMID:22014523	Developmental cell
2022	Medium	ADAMTSL1 marks a distinct myelinating Schwann cell subtype (Pmp2+ SCs) in peripheral nerve that preferentially ensheathes large-caliber motor axons; this subtype is reduced in ALS model mice and human ALS nerve samples.	PMID:35115729	Nature neuroscience
2025	Medium	Ablation of Pmp2+ Schwann cells (co-marked by Adamtsl1) using a tamoxifen-inducible diphtheria toxin system leads to significant loss of large-caliber motor axons with behavioral, electrophysiological, and ultrastructural deficits; withdrawal of tamoxifen restores both PMP2+ SCs and large-caliber motor axons.	PMID:39880678	The Journal of neuroscience
2019	Low	Missense variants in ADAMTSL1 (c.176C>A and c.670C>G) segregate with mandibular prognathism in multiple Thai families; Adamtsl1 is strongly expressed in condensed mesenchymal cells of the mouse condyle but not in long bone cartilage, consistent with a tissue-specific role in mandibular condylar cartilage growth potentially through aggrecan cleavage regulation.	PMID:30714143	Clinical genetics

Citations

PMID:11805097
PMID:18720094
PMID:22014523
PMID:24281761
PMID:24634412
PMID:28722276
PMID:30714143
PMID:34500691
PMID:35115729
PMID:39880678

📚 Additional Documentation

Notes

(ADAMTSL1-notes.md)

ADAMTSL1 (Q8N6G6, punctin-1) — review notes

Human ADAMTSL1, PAINT + affinage campaign. GOA record is unusually small: 4 rows
(1 IEA + 3 TAS), no IBA, no IPI, no MF annotation of any kind.

1. Domain content: the "-like" really does mean non-catalytic

Established from the UniProt feature table before reading any narrative source, because the
campaign has twice shipped an inverted premise about catalysis.

The FT block of ADAMTSL1-uniprot.txt lists, over the 1762-aa precursor: a signal peptide
(1–28), nine annotated TSP type-1 repeats, four Ig-like C2-type domains, and a C-terminal
PLAC domain. There is no metalloprotease domain, no disintegrin-like domain, no
prodomain, and no zinc-binding site feature. There is no CATALYTIC ACTIVITY comment and
no EC number. UniProt states it outright
[file:human/ADAMTSL1/ADAMTSL1-uniprot.txt "lacks the metalloprotease and disintegrin-like domains which are"],
and the primary literature says the same in two places
PMID:11805097
and
PMID:28722276.

So the lead in the task brief holds for this gene, and it is established from the entry's own
feature table rather than from the family name.

The ADAMTS spacer region named in the review description is not an FT DOMAIN feature;
it comes from DR Pfam; PF05986; ADAMTS_spacer1; 1. and DR InterPro; IPR010294; ADAMTS_spacer1.. Sourced in the review's UniProt reference rather than left as an unattributed
claim.

Pfam/PROSITE counts differ from the FT list (PROSITE TSP1 9, SMART TSP1 13, Pfam
TSP1_ADAMTS 11) — the field's usual count for the full-length protein is thirteen TSRs
PMID:28722276.
Nothing in the review depends on the exact repeat count.

2. The peptidase error IS present — but in UniProt's keywords, not in GOA

Q8N6G6 carries KW-0378 Hydrolase (Molecular function category), which generates
[file:human/ADAMTSL1/ADAMTSL1-uniprot.txt "GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW."]
in the entry's own GO cross-reference list
[file:human/ADAMTSL1/ADAMTSL1-uniprot.txt "Extracellular matrix; Glycoprotein; Hydrolase; Immunoglobulin domain;"].

This is contradicted inside the same entry by the CAUTION comment quoted above, and there
is no reaction anywhere in the record to support it.

It is also anomalous within the family. Of the six human ADAMTS-like proteins, only ADAMTSL1
and THSD4 carry the Hydrolase keyword; ADAMTSL2, ADAMTSL3, ADAMTSL4 and ADAMTSL5 carry the
identical CAUTION about the missing metalloprotease domain and no MF keyword. None of the
six has a CATALYTIC ACTIVITY comment. Computed in
[file:human/ADAMTSL1/ADAMTSL1-bioinformatics/RESULTS.md "Entries with a CATALYTIC ACTIVITY comment: none."].

The important curation fact: this never reached GOA. GO:0016787 is absent from
ADAMTSL1-goa.tsv and from QuickGO, because keyword-derived annotations (GO_REF:0000043)
were withdrawn for cellular organisms. So the defect is live in UniProt and invisible in GO.
It is reported in suggested_questions as a UniProt correction to file, not as an
existing_annotations row, because reviewing rows that GOA does not carry would break the
row-count reconciliation.

Two other places the same conflation shows up, worth separating because they have different
standing:

PANTHER's family GO-slim. geneinfo for Q8N6G6 returns GO_SLIM_MF: GO:0004222,
GO_SLIM_BP: GO:0006508, and protein class PC00153 metalloprotease. This is not a
per-gene judgement — the identical slim block is returned for every member queried,
including ADAMTS5 (a real protease) and ADAMTSL2 (which carries an explicit
NOT|enables GO:0004222 in GOA). It is the family summary and it is not negation-aware.
Do not cite it as PANTHER calling ADAMTSL1 a protease.
The primary literature. PMID:30714143 proposes
PMID:30714143
— a mechanism that requires a proteolytic activity ADAMTSL1 does not have. It is labelled a
hypothesis by its authors. The affinage record softens it to "aggrecan cleavage regulation",
which is a different and weaker claim than the paper makes; neither is annotatable.

InterPro2GO got this right. IPR013273 ADAMTS/ADAMTS-like is the only one of ADAMTSL1's
fourteen InterPro entries with a GO mapping, and it maps to GO:0030198 alone — no peptidase
term — even though the signature spans the catalytic ADAMTS proteases. That is the correct
treatment of a signature covering a mechanistically heterogeneous family.

3. PAINT knows catalysis was lost on this branch, and says so on one gene out of six

The cached PAINT table for the family contains two negated rows:

PTHR13723 PTN002673039 GO:0004222 F IKR true PANTHER:PTN000347317
PTHR13723 PTN002673039 GO:0006508 P IRD true PANTHER:PTN000347317

IKR (inferred from key residues) and IRD (inferred from rapid divergence) at node
PTN002673039 block metalloendopeptidase activity and proteolysis from propagating below it.
In GOA that loss surfaces as exactly one annotation — ADAMTSL2's NOT|enables GO:0004222
IBA — and on no other ADAMTS-like member. ADAMTSL1 gets neither the positive term (good) nor
the explicit negation (a missed opportunity: the NOT is the machine-readable form of the
CAUTION comment UniProt already writes).

4. The headline finding: ADAMTSL1 is the only human family member with no `GO:0031012`

PAINT holds GO:0031012 extracellular matrix as an IBD at node PTN000347317. Census over
all 26 human members of PTHR13723:

24 of 26 receive it by IBA from that node.
PAPLN is the other member without the IBA. I first wrote this off as PAINT declining to
overlay an existing direct annotation, which is wrong: PAPLN's only GO:0031012 rows are
IEA and TAS, neither experimental, so redundancy suppression cannot be the reason. The
concurrent ADAMTSL5 review (PR #2305) sharpens it further — three PAPLN orthologs (fly
Ppn, mouse Papln, worm mig-6/ppn-1) are themselves seeds at that node. PAPLN is a
second coverage gap, not an explained omission. The script now derives this rather than
asserting it.
ADAMTSL1 has no GO:0031012 annotation of any kind, from any evidence code.

And the gap is species-specific, not subfamily-specific: mouse Adamtsl1 (Q8BLI0), same
PANTHER subfamily SF157, does receive the IBA from PTN000347317, plus three HDA rows from
matrisome proteomics. Full table in
[file:human/ADAMTSL1/ADAMTSL1-bioinformatics/RESULTS.md "Members with no GO:0031012 annotation of any kind: ADAMTSL1."].

UniProt records the human localisation as experimentally supported by three papers
(ECO:0000269|PubMed:11805097, PubMed:17395588, PubMed:19671700), and independent human
evidence exists:

PMID:11805097
— the observation the protein is named for. Caveat: recombinant epitope-tagged protein in a
heterologous cell line.
PMID:24281761
— endogenous ADAMTSL1 detected in human fibroblast secretomes by TAILS degradomics. This
is the stronger localisation evidence of the two: native protein, native compartment.

So the one gene in the family whose ECM residence is directly shown in human cells is the
one gene in the family with no ECM annotation. Proposed as a NEW row (located_in GO:0031012, IDA, PMID:11805097) rather than left for PAINT, because the human primary
evidence stands on its own.

5. `GO:0030198` extracellular matrix organization (the one IEA)

KEEP_AS_NON_CORE, not ACCEPT. The first draft accepted it and rested the acceptance partly
on the annotation being "well-constructed and unrefuted", which the PR reviewer correctly
identified as absence of contradiction rather than positive support. There is positive
support, but all of it is family-level:

The mapping is well-constructed (§2): IPR013273 → GO:0030198 only.
GO:0030198 is the term the heterogeneous family agrees on. Catalytic ADAMTS members reach
it by proteolysis; ADAMTSL2/ADAMTSL4/THSD4 reach it non-catalytically through fibrillin
microfibril assembly. So the term does not depend on the domain ADAMTSL1 lacks, and it
is the correct level of generality rather than a granularity failure.
PAINT reached the same term independently: GO:0030198 is an IBD at PTN000347317 seeded
by 14 gene sources (11 mouse, 2 fly, 1 worm), and it propagated by IBA to 22 human
members of the family, three of them ADAMTS-like (ADAMTSL2, ADAMTSL4, THSD4). Note the
seed count is 14, not the 15 you get by counting WITH/FROM tokens on the derived IBA rows:
GOA appends the PANTHER node itself to that field. Both figures are now computed by
check_family_propagation.py rather than counted by eye: the 14 in RESULTS.md section 4
(IBD seed composition) and the 22 in section 1 (a second census pass over GO:0030198,
added after the PR reviewer pointed out the script censused only GO:0031012).
But there is no ADAMTSL1-specific evidence for it, and the group that discovered the
protein says so:
PMID:28722276

Kept on those three grounds, with the gap recorded in knowledge_gaps. Being present in the
ECM and being an MMP10 substrate places ADAMTSL1 in ECM remodelling; neither demonstrates
that it organises the matrix. So the term stays, but it is not asserted as this gene's core
function, and core_functions deliberately carries only locations: GO:0031012 — the one
claim the gene's own data establishes.

Divergence from the concurrent ADAMTSL5 review, and a premise that turned out false

PR #2305 (ADAMTSL5) marks the identical InterPro GO:0030198 IEA
MARK_AS_OVER_ANNOTATED. I was told the two positions could both stand because ADAMTSL1 has
the GO:0030198 IBA and ADAMTSL5 does not. That premise is false, and #2305's own table
says so: ADAMTSL1 is – in its GO:0030198 column. My census agrees — the IBA from
PTN000347317 reaches only ADAMTSL2, ADAMTSL4 and THSD4 within the ADAMTS-like branch.
ADAMTSL1 and ADAMTSL5 hold the InterPro IEA and nothing else, i.e. identical evidentiary
positions, and if anything ADAMTSL5 has more gene-specific matrix evidence (its own IDA
to GO:0031012, plus microfibril and heparin binding). The divergence therefore cannot be
justified per gene; it is about where the family draws the KEEP_AS_NON_CORE /
MARK_AS_OVER_ANNOTATED line, and it is filed once in suggested_questions. The script now
asserts the parity so the comparison cannot go stale.

One asymmetry worth recording, raised by the PR reviewer: for GO:0030198 the IBA misses
4 of 26 human members (ADAMTSL1, ADAMTSL3, ADAMTSL5, PAPLN), against 2 of 26 for
GO:0031012. So "coverage gap" is a weaker reading for GO:0030198 than it is for the
headline GO:0031012 finding, and this review does not lean on it — the claim made about
GO:0030198 is only that the IBD node sits above ADAMTSL1, with the propagation pattern
itself filed as a question rather than argued as a defect.

Where the two reviews agree: ADAMTSL1 has no IBA at all (#2305 flagged this as worth
checking against my branch — no discrepancy, my review reports the absence, never IBA
support), and absence of an IBA at an incoherently-propagating node is a coverage gap rather
than a curatorial judgement. My headline uses the absence exactly that way.

6. The `GO:0005788` ER lumen rows (three of them)

All three are true and all three say the same thing. ADAMTSL1's TSRs are O-fucosylated by
POFUT2 and extended by B3GLCT in the ER lumen, and this is required for export
PMID:17395588,
with C-mannosylation acting in the same quality-control step
PMID:19671700.

Reasons for KEEP_AS_NON_CORE rather than ACCEPT:

The ER lumen is a biosynthetic transit compartment; ADAMTSL1 acts in the ECM.
The three rows are one statement from three reactions of one Reactome pathway, and
R-HSA-6785565 is a FailedReaction ("Defective B3GALTL does not transfer glucose to
O-fucosyl-proteins") modelling the Peters-plus disease state — so the third copy is derived
from a reaction that by construction does not occur.
Projection check: each of the three Reactome references annotates ~9 gene products with the
same three terms (GO:0005788, GO:0005789, plus the enzyme's activity). That is
set-membership projection from a pathway participant list, not nine independent findings.

Sibling divergence, declared. The merged ADAMTSL4 review resolved the identical three
rows as ACCEPT, but its own reason reads "This localization reflects its secretory pathway
transit, not a functional localization" — substantively the same judgement, encoded with a
different action. Flagged in suggested_questions for harmonisation rather than silently
diverging.

7. Isoforms — the short form is punctin-1, not the long one

The task brief had this the wrong way round, so stating it plainly: punctin-1 is the SHORT
splice variant (525 aa, UniProt Q8N6G6-1), and the canonical displayed sequence is the
long isoform 3 (1762 aa, Q8N6G6-3)
PMID:28722276.
UniProt applies the AltName "Punctin-1" at entry level, which is where the confusion comes
from; the literature uses it for the short form.

This matters because essentially every ADAMTSL1 experiment was done on isoform 1:

the 2002 purification, rotary shadowing, Edman sequencing, glycosylation analysis and
punctate substratum deposition (mass spectrometry range 28–525);
all O-fucosylation and C-mannosylation site mapping and every secretion mutant
(Trp36/39/42, Trp385, Trp445, Thr312, Ser391, Thr451 — all within residues 1–525);
the Trp42Arg disease-variant secretion assay, explicitly:
PMID:28722276

isoform: Q8N6G6-1 is therefore set on the proposed GO:0031012 row to record what was
tested, per CLAUDE.md's isoform-tracking convention — not to assert the localisation is
isoform-restricted. It almost certainly is not: isoforms 1–4 all retain the signal peptide.
Isoforms 5 and 6 delete residues 1–1299 including the signal peptide (VSP_039322) and so
would not enter the secretory pathway at all, and isoform 5 is flagged as NMD-prone; that
distinction is recorded in functional_isoforms.

Minor tooling bug found: fetch-gene seeded alternative_products with isoform 5's
sequence_note as VSP_039322, VSP_039329, VSP_039330, — the trailing VSP_039331 was
dropped because the UniProt CC block wraps mid-list. Corrected by hand in the review YAML.

8. Checks run, including the ones that came back negative

Retractions / errata / expressions of concern — all twelve PMIDs relied on were checked
via each article's own CommentsCorrections record (a publication-type search does not see
Publisher Corrections). None flagged.
IntAct / partner resolution — 16 interaction records for Q8N6G6, but they reduce to
seven distinct protein partners (ACOX1, B3GLCT, WDCP, FBN2, RSPRY1, FHL2, GRN), each
reported twice because BioPlex 2.0 (PMID:28514442) and BioPlex 3.0 (PMID:33961781) are the
same anti-tag co-IP pipeline; every record is MI-score 0.35 in over-expressing HEK293T, with
no orthogonal assay. One further AP-MS hit (LPAR1, PMID:40205054, U2OS). Several partners are
cytosol- or peroxisome-facing (FHL2, ACOX1) and so compartment-implausible for a
signal-peptide protein. GOA carries zero GO:0005515 rows for ADAMTSL1, and none of this
should be imported. Two hits are worth keeping as hypotheses only: B3GLCT is the enzyme
that glucosylates ADAMTSL1's O-fucosylated TSRs (so the "interaction" is an expected
enzyme–substrate encounter in the ER), and FBN2 would be the first fibrillin link for this
family member.
Complex/reference projection check — applied to the Reactome references (§6). Positive:
they are projections. Not applicable to a literature reference here, since no experimental
GOA row exists.
Sibling-paralog consistency — ADAMTSL4's merged review checked; divergence on the ER
lumen action declared (§6).
Downward-MODIFY check (the ACRV1 pattern) — no IBA rows exist on ADAMTSL1, so there is
no propagation landing above its donor. Negative, by absence of the row class.
Marker-vs-function check — PMID:35115729 and PMID:39880678 use Adamtsl1 purely as a
transcriptional marker of a mouse Pmp2+/Cldn14+ myelinating Schwann cell subtype
PMID:35115729.
PMID:39880678 ablates the cell population, not the gene, so its large-caliber-axon
phenotype is a property of the cell type. Nothing annotatable to ADAMTSL1; deliberately not
proposed.
Worm orthologue — MADD-4 is a secreted midline guidance cue acting through UNC-40/DCC
(PMID:22014523), but that paper itself declines to extend it:
PMID:22014523
Not carried into any human annotation.
Chondrosarcoma — PMID:24634412 reports ADAMTSL1 as a Hedgehog-responsive gene that
"regulates chondrosarcoma cell proliferation". This is the only gene-specific functional
perturbation in the ADAMTSL1 literature, so it is now adjudicated in the review file
with a reference_review, not only here. Declined on three grounds: the cached record is
abstract-only and gives no direction, so neither GO:0008284 nor GO:0008285 can be
chosen; the assay is a cancer cell line with no normal-physiology counterpart; and a
proliferation phenotype narrows neither recorded gap, since it identifies no molecular
function and says nothing about matrix organisation. It does mean the review's "nothing is
known" claim must be stated precisely — no molecular function and no matrix-organisation
evidence, rather than no functional observation of any kind. PMID:39880678 is likewise
now a references entry rather than a notes-only mention.

8b. The one molecular-function experiment ever done on ADAMTSL1, and it is negative

Found late, and not by me: the concurrent ADAMTSL3 review surfaced it. PMID:22242013 is
titled "Microenvironmental regulation by fibrillin-1", so no ADAMTSL1-keyed search reaches
it; it is absent from ADAMTSL1's GOA and from the affinage record. It is the campaign's
"a paper titled for something else holds your gene's answer" lesson in its partner-named form.

Two direct SPR negatives for human ADAMTSL1, in a panel where its relatives were positive:

This is a measured negative, not an absence, which makes it much stronger than the silence
this review was otherwise working against.

Only the fibrillin-1 half is discriminating, and the PR reviewer was right that my first
write-up read as two independent exclusions. ADAMTSL-2 is equally negative against ADAMTS-10
and still reaches GO:0030198; ADAMTS-10 binding was shown only for ADAMTSL-3; THSD4 was never
tested against it. So the ADAMTS-10 result does not separate ADAMTSL1 from its relatives and
must not be double-counted. The fibrillin-1 negative alone carries the argument, and it is
enough.

The caveat is the isoform question again. The methods say
"Recombinant full length ADAMTSL-1, -2, LTBP-1, -4 ... were covalently coupled to CM5 sensor
chips" but never give a length, and the Apte lab stated five years later that no construct
for the 1762-residue form existed. Both RefSeqs were available in 2012 (NP_443098 = isoform 1,
525 aa; NP_001035362 = isoform 3, 1762 aa), so the paper alone does not settle it, and the
balance of evidence favours punctin-1. Recorded as a bounded negative: firm for whatever
was assayed, and probably untested for the nine extra TSRs, four Ig-like domains and PLAC
domain of the long form.

What it changed in this review. Ground two of the GO:0030198 reason — "a non-catalytic
route to the term is available to this architecture" — is now explicitly qualified, because
the specific route the relatives use is excluded for this protein. It does not flip the verdict
to MARK_AS_OVER_ANNOTATED: GO:0030198 is far broader than fibrillin-1 binding, and
excluding one mechanism is not refuting the process. But it removes the strongest mechanistic
analogy, and it is a further reason the term cannot be called core. The MF knowledge_gap is
now bounded on both sides — what is established, and what has been measured and excluded —
and the proposed binding experiment became an unbiased partner search rather than the
candidate SPR I had originally proposed, which would have repeated a published negative.

One more correction from the same round, and it is the lesson of this section applied to
itself: I wrote that "the LTBPs remain untested". Unsafe. LTBP-1 and LTBP-4 were coupled to
CM5 chips in these very experiments, and the LTBP results sit in a supplementary table that is
not in the cached record. "Not reported in the main text" is what the evidence supports. This
whole section exists because a candidate that looked untested turned out to have been tested,
so asserting a second one untested on the same paper would have been the same error twice.

And the parity claim needed narrowing. I had written that ADAMTSL1 and ADAMTSL5 are "in
exactly the same evidentiary position" for GO:0030198. That was true when I wrote it and this
paper made it false: the two remain in the same IBA position, but ADAMTSL5 has its own IDA to
GO:0031012 plus microfibril and heparin binding, while ADAMTSL1 now carries a measured
negative against the route by which the family reaches GO:0030198. The difference runs
against this review, not for it — the better-supported gene is the one taking the harsher
action. That does not change the verdict here, but it converts the family-wide line-drawing
question from a tie into an argument, and it is carried into suggested_questions as such.

8c. A gap in `checkquotes.py` worth knowing about

Reconciling a count that did not add up (I added three quotes and the checker's total rose by
one) turned up a real scope gap rather than an arithmetic slip. checkquotes.py walks
supported_by and findings only; provenance lists inside knowledge_gaps are invisible
to it, as is any other reference_id + supporting_text pair under a differently-named key.
For this file: 17 supported_by + 32 findings = 49, exactly what the checker reports, and
6 provenance quotes are unchecked. They were verified here with a walker that matches on
the shape of the entry rather than on its parent key, and all 6 pass. Anyone relying on
checkquotes.py alone for a review that uses knowledge_gaps provenance is not checking those
quotes.

But it is a local-script gap, not a project-gate gap — I initially implied the wider risk and
that was wrong. The gate that actually runs in CI is linkml-reference-validator via
just validate, and it does walk provenance. Established by breaking it rather than by reading
code: injecting THIS SENTENCE APPEARS IN NO PUBLICATION ANYWHERE ZZQQXX. as a provenance
supporting_text turns just validate from ✓ Valid into
✗ Invalid ... Text part not found as substring. The probe asserted its anchor was present before
mutating, and the file was restored to a clean git diff afterwards. So provenance quotes in this
repo are gated; it is only the scratch checker that misses them.

8d. The recurring defect in this review, and what finally caught it

Five of the review rounds on this gene found the same defect shape: a claim corrected in the
field I was thinking about and left standing in a parallel field saying the same thing elsewhere.
The instances were the GO:0030198 reason vs core_functions; the top-level MF gap boundary vs
the nested BP gap boundary; the suggested_questions tail vs its own narrowed opening; the
knowledge_gaps resolution vs suggested_experiments; and the reference findings statement vs
the row reason. The reviewer caught four. The fifth I found only by giving up on per-field
fixes and sweeping the whole parsed document for every phrasing I had ever retracted — it was
in the top-level MF boundary, which had already been rewritten twice without anyone noticing the
old double-count framing still sitting in it.

The sweep is seven regexes run over every string value in the parsed YAML:

two partners that place | both been tested for ADAMTSL1 and both were negative |
exactly the same evidentiary position | well-constructed and unrefuted |
LTBPs remain untested | no positive binding result of any kind |
divergence is not attributable to a difference between the genes

It is the ACBD3 lesson (a claim asserted at N sites with no generation relationship between
them) in a review that had read that lesson and still reproduced it five times. The transferable
part is not "be careful": it is that the unit of correction has to be the document, not the
field, and a retraction list scanned over all prose is cheap enough to run on every round.

And the sweep is only half the control. The commit that fixed instances 1-5 produced a
sixth of the same shape: a (data not shown) caveat added to the reference findings and to
the row reason but not to the nested BP boundary. A retraction list structurally cannot catch
that — it looks for old phrasing left standing, whereas this is new phrasing propagated
to some siblings and not others. The complementary check has to run at write time and enumerate
the siblings: for the C-terminal widening the sibling set is references.findings[1],
existing_annotations[0].review.reason and
existing_annotations[0].review.knowledge_gaps[0].boundary, and the edit now asserts that both
the claim and its caveat appear in all three before it is accepted. Two directions, two
checks: sweep for what should be gone, assert co-occurrence for what should be everywhere.

And the co-occurrence check failed too, for the reason the reviewer named: it is only as good
as the hand-authored sibling list, and enumerating siblings is the same judgement that produced
the six instances. My list had three members; the widened claim was load-bearing in a fourth —
the top-level MF boundary, which concluded "what is excluded is fibrillin-1 binding" while
stating the evidence as the N-terminal half only, so the field used the widened scope without
carrying what licenses it. Three of four beats the sweep alone, but the residual failure mode
survived the new control.

The fix is to stop hand-listing. Derive the sibling set from the document: collect every
string field, select those that draw the widened conclusion (excluded is fibrillin-1 binding
or covers fibrillin-1 entire), and require each to state the basis (C-terminal half). That
found the missing field immediately and now passes on three. Two further guards make the check
non-vacuous: it asserts the selector matched something at all, and the selector keys on the
conclusion rather than on a list of field paths, so a claim copied into a new field is caught
automatically. Generalisable form: select the fields by what they assert, not by where they
live.

And that control leaked too, in a smaller way — which turns out to be the real finding. The
selector matched two fixed English phrasings, so it missed the reference findings statement,
which draws the same conclusion as "covers fibrillin-1 in its entirety, not only the N-terminal
half". Nothing was wrong in the file — that field carried the basis and the caveat and passed on
merit — but had the caveat later been dropped from it, the check would still have reported all
green, because the field asserting the conclusion in different words was never selected. Matching
on fixed phrasings is still selecting by how a field asserts something; it is one abstraction
level up from a path list, not a different kind of thing. Broadened to four patterns, and the
selected set went 3 → 4.

The pattern across the whole review is the point. Each control caught one more instance than
its predecessor and left a smaller version of the same gap:

control	caught	residual gap
fix the field in front of me	1 at a time	5 parallel fields left stale
retraction sweep over all prose	the 5th instance	cannot see new phrasing propagated unevenly
hand-listed sibling co-occurrence	3 of 4 siblings	list is the same judgement that caused the defect
conclusion-derived selector	the 4th sibling	selector is phrase-literal, misses paraphrase
broadened phrase set	the paraphrase	still phrase-literal in principle

No text-matching control closes this completely, because the thing being checked is whether two
sentences mean the same. The honest summary is that each round bought a real reduction and none
of them bought closure, and that a reviewer reading the parsed fields end to end caught what
every mechanical control missed.
Note the notes file legitimately still contains three of those strings, because explaining why a
phrasing was retracted requires quoting it — so the sweep belongs on the review YAML, not on
prose that discusses it.

9. What ADAMTSL1 is, in one paragraph

A large secreted ADAMTS-like glycoprotein of the extracellular matrix, built from
thrombospondin type-1 repeats, Ig-like C2-type domains and a PLAC domain, with none of the
catalytic machinery of the ADAMTS proteases. Its biosynthesis is unusually
glycosylation-dependent: O-fucosylation of the TSRs by POFUT2 with B3GLCT extension, and
C-mannosylation of TSR1 tryptophans, together gate export from the ER, and a natural
Trp42Arg substitution at a C-mannosylation site blocks secretion and acts dominant-negatively
in a family with congenital glaucoma, craniofacial, dental, auditory, renal and limb
anomalies. Once secreted it is deposited punctately into the matrix and is a substrate of
MMP10 in fibroblast secretomes. Its molecular function is undetermined.

Bioinformatics Results

(RESULTS.md)

PTHR13723 annotation census for ADAMTSL1

Regenerate with:

uv run genes/human/ADAMTSL1/ADAMTSL1-bioinformatics/check_family_propagation.py

Retrieval timestamp is recorded in results.json so this file stays byte-reproducible.

1. `GO:0031012` coverage across human PTHR13723

PAINT holds GO:0031012 as an IBD annotation at node PTN000347317. Of the 26 human members of the family, 24 receive it by IBA from that node.

gene	accession	subfamily	GO:0031012 IBA	other rows	evidence codes	GO:0030198 IBA	GO:0030198 other
ADAMTS1	Q9UHI8	PTHR13723:SF40	1	2	HDA, IBA, IEA	1	IBA, IEA
ADAMTS10	Q9H324	PTHR13723:SF26	1	1	IBA, IDA	1	IBA, IEA
ADAMTS12	P58397	PTHR13723:SF189	1	0	IBA	1	IBA, IEA
ADAMTS13	Q76LX8	PTHR13723:SF20	1	1	IBA, TAS	1	IBA, IEA
ADAMTS14	Q8WXS8	PTHR13723:SF24	1	0	IBA	1	IBA, IEA, TAS
ADAMTS15	Q8TE58	PTHR13723:SF39	1	1	IBA, IEA	1	IBA, IEA, ISS
ADAMTS16	Q8TE57	PTHR13723:SF140	1	0	IBA	1	IBA, IEA
ADAMTS17	Q8TE56	PTHR13723:SF151	1	1	IBA, IDA	1	IBA, IEA
ADAMTS18	Q8TE60	PTHR13723:SF167	1	0	IBA	1	IBA, IEA
ADAMTS19	Q8TE59	PTHR13723:SF197	1	0	IBA	1	IBA, IEA, ISS
ADAMTS2	O95450	PTHR13723:SF141	1	1	IBA, IEA	1	IBA, IEA, TAS
ADAMTS20	P59510	PTHR13723:SF165	1	1	IBA, TAS	1	IBA, IEA
ADAMTS3	O15072	PTHR13723:SF158	1	2	IBA, NAS, TAS	1	IBA, IC, IEA, NAS, TAS
ADAMTS4	O75173	PTHR13723:SF38	1	1	HDA, IBA	1	IBA, IEA, TAS
ADAMTS5	Q9UNA0	PTHR13723:SF37	1	2	IBA, IEA, TAS	1	IBA, IEA, ISS, TAS
ADAMTS6	Q9UKP5	PTHR13723:SF27	1	0	IBA	1	IBA, IEA
ADAMTS7	Q9UKP4	PTHR13723:SF142	1	1	IBA, IEA	1	IBA, IEA
ADAMTS8	Q9UP79	PTHR13723:SF41	1	2	IBA, IEA, ISS	1	IBA, IEA
ADAMTS9	Q9P2N4	PTHR13723:SF33	1	2	IBA, IDA, ISS	1	IBA, IEA, ISS
ADAMTSL1	Q8N6G6	PTHR13723:SF157	0	0	-	0	IEA
ADAMTSL2	Q86TH1	PTHR13723:SF147	1	0	IBA	1	IBA, IEA
ADAMTSL3	P82987	PTHR13723:SF169	1	1	IBA, TAS	0	IEA
ADAMTSL4	Q6UY14	PTHR13723:SF144	1	3	HDA, IBA, TAS	1	IBA
ADAMTSL5	Q6ZMM2	PTHR13723:SF173	1	3	IBA, IDA, TAS	0	IEA
PAPLN	O95428	PTHR13723:SF281	0	2	IEA, TAS	0	IEA
THSD4	Q6ZMP0	PTHR13723:SF16	1	10	HDA, IBA, IEA, RCA, TAS	1	IBA
Adamtsl1 (mouse)	Q8BLI0	PTHR13723:SF157	1	3	HDA, IBA	0	IEA

Members with no GO:0031012 annotation of any kind: ADAMTSL1.

PAPLN holds GO:0031012 without the IBA, but none of its rows is experimental (evidence codes: IEA, TAS), so redundancy suppression does not account for the missing IBA. Its absent IBA is a second coverage gap at this node, not an explained omission.

ADAMTSL1 has neither an IBA nor any other row, and its mouse orthologue - the same PANTHER subfamily, the same IBD node - does receive the IBA.

`GO:0030198` coverage, same node

22 of the 26 human members receive GO:0030198 by IBA from PTN000347317: ADAMTS1, ADAMTS10, ADAMTS12, ADAMTS13, ADAMTS14, ADAMTS15, ADAMTS16, ADAMTS17, ADAMTS18, ADAMTS19, ADAMTS2, ADAMTS20, ADAMTS3, ADAMTS4, ADAMTS5, ADAMTS6, ADAMTS7, ADAMTS8, ADAMTS9, ADAMTSL2, ADAMTSL4, THSD4. Members with no GO:0030198 annotation at all: none.

Within the ADAMTS-like branch the IBA reaches only ADAMTSL2, ADAMTSL4, THSD4. ADAMTSL1 and ADAMTSL5 are therefore in the same position for this term - the InterPro IEA and nothing else - which matters when comparing verdicts between their reviews.

2. `Hydrolase` keyword across the ADAMTS-like branch

UniProt's KW-0378 Hydrolase is what generates the GO:0016787 hydrolase activity cross-reference in an entry's own GO list (IEA:UniProtKB-KW).

gene	accession	length	MF keywords	CAUTION: no metalloprotease domain
ADAMTSL1	Q8N6G6	1762	Hydrolase	yes
ADAMTSL2	Q86TH1	951	-	yes
ADAMTSL3	P82987	1691	-	yes
ADAMTSL4	Q6UY14	1074	-	yes
ADAMTSL5	Q6ZMM2	481	Heparin-binding	yes
THSD4	Q6ZMP0	1018	Hydrolase	no

Hydrolase keyword present on: ADAMTSL1, THSD4. CAUTION stating the metalloprotease and disintegrin-like domains are absent: ADAMTSL1, ADAMTSL2, ADAMTSL3, ADAMTSL4, ADAMTSL5 (absent on THSD4).

Entries with a CATALYTIC ACTIVITY comment: none. So on ADAMTSL1 the keyword sits alongside that entry's own statement that the catalytic domain is missing, with no reaction recorded anywhere in the entry.

3. PAINT's own loss calls in this family

The cached PAINT table records explicitly negated annotations, i.e. terms PAINT blocks from propagating below a node:

node	term	aspect	evidence	seed
PTN002673039	GO:0004222	F	IKR	PANTHER:PTN000347317
PTN002673039	GO:0006508	P	IRD	PANTHER:PTN000347317

IKR is inferred-from-key-residues and IRD inferred-from-rapid-divergence: PAINT has judged that catalysis was lost on this branch. Where those calls land in GOA:

gene	GO:0004222 rows	GO:0006508 rows
ADAMTSL1	none	none
ADAMTSL2	`NOT\\|enables` IBA GO_REF:0000033	none
ADAMTSL3	none	none
ADAMTSL4	none	none
ADAMTSL5	none	none
THSD4	none	none

Negated rows in GOA: ADAMTSL2 GO:0004222. Positive rows in GOA: none. So the loss call is recorded for part of the branch and simply absent for the rest - ADAMTSL1 inherits neither the catalytic terms nor the statement that they do not apply.

4. IBD seed composition at the family node

Counting WITH/FROM tokens on the derived IBA rows overstates the number of experimental sources by one, because GOA appends the PANTHER node itself to the list. The seed lists in the PAINT table give the gene sources directly:

node	term	aspect	evidence	seed tokens	gene sources	by database
PTN000347317	GO:0031012	C	IBD	16	16	FB 2, MGI 8, RGD 1, UniProtKB 4, WB 1
PTN000347317	GO:0004222	F	IBD	9	9	MGI 3, UniProtKB 6
PTN000347317	GO:0006508	P	IBD	13	13	MGI 7, UniProtKB 4, ZFIN 2
PTN000347317	GO:0030198	P	IBD	14	14	FB 2, MGI 11, WB 1

Guards

The script aborts rather than emitting a stale sentence if any of these stop holding: a QuickGO response is paginated (page total read as the whole set); human ADAMTSL1 acquires any GO:0031012 row; mouse Adamtsl1 loses its IBA from PTN000347317; ADAMTSL1 loses KW-0378, gains a CATALYTIC ACTIVITY comment, or loses the CAUTION about the missing metalloprotease domain; the IKR loss call disappears from the cached PAINT table; or ADAMTSL1 gains a GO:0004222/GO:0006508 row. A missing cached input is a hard error naming the command that regenerates it. The zero-row count for ADAMTSL1 is produced by the same code path that returns non-zero for the other 25 human members on every run, so the census is its own positive control.

📄 View Raw YAML

id: Q8N6G6
gene_symbol: ADAMTSL1
product_type: PROTEIN
status: COMPLETE
aliases:
- ADAMTSL-1
- Punctin-1
- ADAMTSR1
- C9orf94
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ADAMTSL1 is a large secreted glycoprotein of the extracellular matrix and the prototype of
  the ADAMTS-like family. It is built entirely from the ancillary modules of the ADAMTS
  proteases - thrombospondin type-1 repeats, four immunoglobulin-like C2-type domains, an
  ADAMTS spacer region and a C-terminal PLAC domain - and lacks the prodomain, the
  metalloprotease domain and the disintegrin-like domain, so it is not itself a protease.
  Its biosynthesis is unusually dependent on glycosylation of the thrombospondin repeats:
  O-fucosylation by POFUT2 with subsequent glucose addition by B3GLCT, together with
  C-mannosylation of tryptophans in the first repeat, act as a quality-control gate on export
  from the endoplasmic reticulum, and disrupting either modification traps the protein inside
  the cell. Once secreted, the protein is deposited into the pericellular matrix in a
  punctate pattern that gave it the name punctin, and it is cleaved by MMP10 in fibroblast
  secretomes. The gene is expressed most strongly in adult skeletal muscle, with additional
  expression in ocular anterior-segment tissues, the mandibular condyle and a myelinating
  Schwann cell subtype. A heterozygous substitution at a C-mannosylation site blocks
  secretion and acts dominant-negatively in a pedigree with congenital glaucoma together with
  craniofacial, dental, auditory, renal, brain-vascular and limb anomalies, and other
  missense variants segregate with mandibular prognathism. Its molecular function and binding
  partners are undetermined; by analogy with other ADAMTS-like proteins it is expected to act
  in the assembly or turnover of the extracellular matrix, but this has not been demonstrated
  for ADAMTSL1 itself.
alternative_products:
- name: '3'
  id: Q8N6G6-3
  description: Canonical displayed sequence, 1762 aa full-length protein.
- name: '1'
  id: Q8N6G6-1
  sequence_note: VSP_039326
  description: >-
    Short 525-aa splice form, the protein originally described as punctin-1. Carries the
    signal peptide and the first four thrombospondin type-1 repeats. Essentially all
    published ADAMTSL1 biochemistry was performed on this form.
- name: '2'
  id: Q8N6G6-2
  sequence_note: VSP_039323, VSP_039324, VSP_039325
- name: '4'
  id: Q8N6G6-4
  sequence_note: VSP_039327, VSP_039328
- name: '5'
  id: Q8N6G6-5
  sequence_note: VSP_039322, VSP_039329, VSP_039330, VSP_039331
  description: >-
    Lacks residues 1-1299, including the signal peptide. UniProt notes it may be produced at
    very low levels because of a premature stop codon triggering nonsense-mediated decay.
- name: '6'
  id: Q8N6G6-6
  sequence_note: VSP_039322, VSP_039329
  description: Lacks residues 1-1299, including the signal peptide.
functional_isoforms:
- id: ADAMTSL1_PUNCTIN1_SHORT
  name: Punctin-1 (short form)
  type: SPLICE_VARIANT
  maps_to:
  - type: UNIPROT_ISOFORM
    ids:
    - Q8N6G6-1
  description: >-
    The 525-amino-acid splice form that the literature calls punctin-1, comprising the signal
    peptide and the first four thrombospondin type-1 repeats. It is the form that was
    purified and characterised in 2002, the form in which every O-fucosylation and
    C-mannosylation site was mapped, the form carrying all published secretion mutants, and
    the form used to test the Trp42Arg disease variant. Note that UniProt lists Punctin-1 as
    an alternative name for the whole entry while the canonical displayed sequence is the
    1762-amino-acid isoform 3, so "punctin-1" in the literature and "Punctin-1" in UniProt
    refer to different things. No functional difference from the long form has been
    demonstrated; the distinction here is one of experimental coverage, not of known biology.
- id: ADAMTSL1_SIGNAL_PEPTIDE_LESS
  name: Signal-peptide-less isoforms 5 and 6
  type: SPLICE_VARIANT
  maps_to:
  - type: UNIPROT_ISOFORM
    ids:
    - Q8N6G6-5
    - Q8N6G6-6
  description: >-
    Both isoforms delete residues 1-1299 (VSP_039322), removing the signal peptide, so
    neither is expected to enter the secretory pathway or reach the extracellular matrix.
    Isoform 5 is additionally flagged by UniProt as a likely target of nonsense-mediated
    decay. Secretion-dependent and extracellular annotations on this gene should not be read
    as applying to these two forms.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings:
  - statement: >-
      The only InterPro entry matched by ADAMTSL1 that carries a GO mapping is IPR013273
      (ADAMTS/ADAMTS-like), and it maps to GO:0030198 extracellular matrix organization
      alone. Although the signature spans the catalytic ADAMTS metalloproteases, the mapping
      does not include any peptidase or hydrolase term, so no catalytic activity is
      propagated to the non-catalytic members of the family through this route.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Checked against the current interpro2go release: IPR013273 maps only to GO:0030198, and
      none of ADAMTSL1's other thirteen InterPro entries carries any GO mapping.
- id: Reactome:R-HSA-5173005
  title: B3GALTL transfers glucose to O-fucosyl-proteins
  findings:
  - statement: >-
      Reaction of the O-glycosylation of TSR domain-containing proteins pathway in which
      B3GLCT, an ER membrane enzyme, adds glucose to the O-fucose already present on
      thrombospondin type-1 repeats. ADAMTSL1 is a member of the O-fuc-proteins participant
      set, which Reactome places in the endoplasmic reticulum lumen.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reaction record fetched from the Reactome content service; compartments are
      endoplasmic reticulum membrane and endoplasmic reticulum lumen, and the catalyst is
      B3GLCT. The underlying claim for ADAMTSL1 is experimentally supported by PMID:17395588,
      which detected the fucose-glucose disaccharide on TSR2, TSR3 and TSR4 of punctin-1.
- id: Reactome:R-HSA-5173192
  title: POFUT2 transfers fucose to TSR domain-containing proteins
  findings:
  - statement: >-
      Reaction in which the ER-resident enzyme POFUT2 attaches fucose to the conserved Ser or
      Thr of thrombospondin type-1 repeats. ADAMTSL1 is a member of the POFUT2 substrates
      participant set, placed by Reactome in the endoplasmic reticulum lumen.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reaction record fetched from the Reactome content service. Directly corroborated for
      ADAMTSL1 by PMID:17395588.
- id: Reactome:R-HSA-6785565
  title: Defective B3GALTL does not transfer glucose to O-fucosyl-proteins
  findings:
  - statement: >-
      A Reactome FailedReaction modelling the Peters-plus syndrome disease state, in which
      the B3GALTL G393E variant fails to glucosylate O-fucosylated thrombospondin repeats.
      ADAMTSL1 appears as an input to a reaction that by construction does not proceed, yet
      the GO pipeline emits the same endoplasmic reticulum lumen location as for the working
      reaction.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Confirmed as schemaClass FailedReaction via the Reactome content service. The location
      it asserts for ADAMTSL1 is not wrong, but it is the third identical copy of one
      statement and carries no information the two working reactions do not already supply.
- id: PMID:11805097
  title: Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extracellular matrix.
  findings:
  - statement: >-
      Punctin/ADAMTSL-1 is a secreted glycoprotein resembling the ADAMTS proteases but lacking
      the pro-metalloprotease and disintegrin-like domains, and containing four thrombospondin
      type-1 repeats in the short form that was purified.
    supporting_text: >-
      Punctin lacks the pro-metalloprotease and the disintegrin-like domain typical of this
      family but contains other ADAMTS domains in precise order including four thrombospondin
      type I repeats.
    reference_section_type: ABSTRACT
  - statement: >-
      Recombinant punctin expressed in transfected COS-1 cells is deposited into the cell
      substratum in a punctate pattern and is excluded from focal contacts. This is the
      observation that gave the protein its name and the primary human evidence that it
      reaches the extracellular matrix.
    supporting_text: >-
      In transfected COS-1 cells, punctin is deposited in the cell substratum in a punctate
      fashion and is excluded from focal contacts.
    reference_section_type: ABSTRACT
  - statement: >-
      The gene is expressed in adult skeletal muscle, and the authors present punctin as the
      founding member of the ADAMTS-like family whose matrix function was at that point
      prospective rather than demonstrated.
    supporting_text: >-
      Punctin is the first member of a novel family of ADAMTS-like proteins that may have
      important functions in the extracellular matrix.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding description of the protein, cited by UniProt with ECO:0000269 for subunit,
      subcellular location, tissue specificity, glycosylation, mass spectrometry and
      disulfide bonds. Cached record is abstract-only. The localisation caveat that must
      travel with it is that the assay used epitope-tagged recombinant protein in a
      heterologous cell line.
- id: PMID:17395588
  title: 'O-fucosylation of thrombospondin type 1 repeats in ADAMTS-like-1/punctin-1
    regulates secretion: implications for the ADAMTS superfamily.'
  findings:
  - statement: >-
      The thrombospondin repeats of punctin-1 carry POFUT2-type O-fucose, extended in TSR2,
      TSR3 and TSR4 to a fucose-glucose disaccharide, and mutating the modified Ser/Thr
      residues reduces the amount of protein secreted. This is the experimental basis for
      ADAMTSL1's participation in the two Reactome ER-lumen glycosylation reactions.
    supporting_text: >-
      Mutation of the putative modified Ser/Thr residues in TSR2, TSR3, and TSR4 led to
      significantly decreased levels of secreted punctin-1.
    reference_section_type: ABSTRACT
  - statement: >-
      N-glycosylation and O-fucosylation together are required for efficient biosynthesis of
      the protein.
    supporting_text: >-
      the data define a critical role for N-glycosylation and O-fucosylation in the
      biosynthesis of punctin-1
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cited by UniProt with ECO:0000269 for four glycosylation sites and for subcellular
      location. Cached record is abstract-only; the claims used here are all stated in the
      abstract. Experiments were performed on the short punctin-1 form.
- id: PMID:19671700
  title: Post-translational modification of thrombospondin type-1 repeats in ADAMTS-like
    1/punctin-1 by C-mannosylation of tryptophan.
  findings:
  - statement: >-
      Trp39 and Trp42 of the first thrombospondin repeat carry C-linked mannose, adjacent to
      the O-fucose site, and substituting these tryptophans changes secretion efficiency. The
      authors conclude that the two modifications together act as a quality-control mechanism
      on export.
    supporting_text: >-
      Together, these modifications appear to provide a quality control mechanism for
      punctin-1 secretion.
    reference_section_type: ABSTRACT
  - statement: >-
      Mass spectrometry of recombinant human punctin-1 identified the TSR1 peptide spanning
      residues 36-49 bearing two mannose residues and a Glc-Fuc disaccharide.
    supporting_text: >-
      Analysis of tryptic fragments of recombinant human punctin-1 by mass spectrometry
      identified a peptide derived from TSR1 containing the (36)WDAWGPWSECSRTC(49) sequence
      of interest modified with two mannose residues and a Glc-Fuc disaccharide
      (O-fucosylation).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cited by UniProt with ECO:0000269 for three carbohydrate sites, five mutagenesis
      entries and subcellular location. Cached record is abstract-only.
- id: PMID:24281761
  title: Time-resolved analysis of the matrix metalloproteinase 10 substrate degradome.
  findings:
  - statement: >-
      Endogenous ADAMTSL1 was identified in human fibroblast secretomes by terminal amine
      isotopic labelling of substrates and shown to be a direct MMP10 substrate. This places
      native, untagged ADAMTSL1 in the extracellular compartment of a primary human cell type
      and shows it is subject to extracellular proteolysis rather than performing it.
    supporting_text: >-
      we identified the extracellular matrix protein ADAMTS-like protein 1 (ADAMTSL1) as a
      direct MMP10 substrate
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in the cache, but the ADAMTSL1 result is stated in the abstract and named
      as one of the paper's three headline findings. Independent of the 2002 tagged-construct
      localisation, which is why it is used as corroboration for the proposed GO:0031012 row.
- id: PMID:28722276
  title: Identification and functional analysis of an ADAMTSL1 variant associated with a
    complex phenotype including congenital glaucoma, craniofacial, and other systemic features
    in a three-generation human pedigree.
  findings:
  - statement: >-
      The ADAMTS-like proteins are defined as comprising the ADAMTS ancillary domains while
      lacking the protease domain, and therefore lacking enzymatic activity.
    supporting_text: >-
      it also contains a family of seven ADAMTS-like proteins (ADAMTSL family) comprising an
      ADAMTS ancillary domain but lacking the protease domain and thus, enzymatic activity
    reference_section_type: RESULTS
  - statement: >-
      Full-length ADAMTSL1 has thirteen thrombospondin type-1 repeats, four Ig-like C2-type
      domains and one PLAC domain over 1762 residues, and punctin-1 is the 525-residue short
      splice variant with four repeats.
    supporting_text: >-
      Despite being the prototypic ADAMTSL, little is currently known about ADAMTSL1, which
      contains thirteen thrombospondin type 1 repeats (TSRs), four Immunoglobulin-like C2-type
      domains and a single PLAC (protease and lacunin) domain in its full-length form (1762
      amino acids) and four TSRs in a short splice variant named punctin-1 (525 amino acids)
    reference_section_type: RESULTS
  - statement: >-
      The group that discovered the protein states that its tissue function is unknown and
      that a role in matrix assembly and turnover is an expectation drawn from other family
      members rather than an ADAMTSL1 result.
    supporting_text: >-
      The function of punctin-1 in tissues is currently unknown, however, by analogy with
      other family members (Apte 2009; Dubail and Apte 2015; Hubmacher and Apte 2015), there
      is a strong possibility that it mediates the assembly and turnover of extracellular
      matrix at the affected sites.
    reference_section_type: DISCUSSION
  - statement: >-
      A heterozygous p.Trp42Arg allele at a C-mannosylation site cosegregates with a
      multisystem phenotype; the mutant protein is retained intracellularly and also reduces
      secretion of cotransfected wild-type protein.
    supporting_text: >-
      p.Trp42Arg punctin-1 was not secreted and accumulated in cells and 2) in the presence of
      the mutant construct, wild-type punctin-1 was secreted at reduced levels and also
      accumulated intracellularly
    reference_section_type: RESULTS
  - statement: >-
      All of the functional work was done on the short punctin-1 form because no full-length
      expression construct existed, which is why the experimental coverage of this gene is
      confined to isoform Q8N6G6-1.
    supporting_text: A plasmid construct for full-length ADAMTSL1 is presently unavailable.
    reference_section_type: DISCUSSION
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available in the cache and read in full. Co-authored by the Apte laboratory,
      which discovered the protein, so its explicit statement that the tissue function is
      unknown is an authoritative negative and not an omission.
- id: PMID:22014523
  title: MADD-4 is a secreted cue required for midline-oriented guidance in Caenorhabditis
    elegans.
  findings:
  - statement: >-
      MADD-4, the C. elegans protein most closely related to ADAMTSL1 and ADAMTSL3, is a
      secreted guidance cue acting through the netrin receptor UNC-40/DCC. The authors
      explicitly decline to extend a biological role to the mammalian orthologues.
    supporting_text: >-
      The biological role of MADD-4 orthologs, including ADAMTSL1 and 3 in mammals, is
      unknown.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Used only for the family-level context and for the authors' own statement that the
      mammalian role is unknown. Nothing from the nematode phenotype is carried into a human
      annotation.
- id: PMID:30714143
  title: ADAMTSL1 and mandibular prognathism.
  findings:
  - statement: >-
      Two rare ADAMTSL1 missense variants segregate with mandibular prognathism in Thai
      families, and mouse Adamtsl1 is expressed in the condensed mesenchyme of the condyle
      but not in long-bone cartilage. The mechanism the authors propose requires ADAMTSL1 to
      cleave aggrecan, an activity the protein's domain content does not support, and they
      label it a hypothesis.
    supporting_text: >-
      We hypothesize that mutations in ADAMTSL1 cause failure to cleave aggrecan in the
      condylar cartilage, and that leads to overgrowth of the mandible.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: DISPUTED
    review_notes: >-
      The genetic association is reported without functional validation, and the proposed
      mechanism attributes proteolysis to a protein that has no metalloprotease domain, no
      catalytic activity comment and no EC number. Cited here as an example of the
      family-name-to-activity conflation, not as evidence for any annotation.
- id: PMID:35115729
  title: Disentangling glial diversity in peripheral nerves at single-nuclei resolution.
  findings:
  - statement: >-
      Adamtsl1 is used as one of three transcriptional markers defining a myelinating Schwann
      cell subtype in mouse peripheral nerve that preferentially ensheathes motor axons. The
      gene's own function is not assayed.
    supporting_text: >-
      including a subtype characterized by expression of Pmp2, Adamtsl1 and Cldn14 that
      preferentially myelinates motor axons
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Full text available and searched. Every mention of Adamtsl1 is as a cluster marker;
      there is no perturbation of the gene. Recorded so that a later reviewer does not mistake
      marker expression for a function, and so the companion cell-ablation study
      (PMID:39880678) is read as a property of the cell type rather than of the gene.
- id: PMID:22242013
  title: Microenvironmental regulation by fibrillin-1.
  findings:
  - statement: >-
      Surface plasmon resonance with recombinant human ADAMTSL-1, -2 and -3 against the
      N-terminal half of fibrillin-1 found that ADAMTSL-2 and -3 bound and ADAMTSL-1 did not.
      This is a direct, measured negative for ADAMTSL1 against the partner through which the
      other ADAMTS-like proteins reach the extracellular matrix organization term.
    supporting_text: >-
      ADAMTSL-2, -3, and papilin polypeptides interacted with the N-terminal half of
      fibrillin-1, while ADAMTSL-1 did not.
    reference_section_type: RESULTS
  - statement: >-
      The negative covers fibrillin-1 in its entirety, not only the N-terminal half: binding
      to the C-terminal half was negative for every ADAMTSL protein in the panel. Held to a
      lower evidentiary standard than the N-terminal result, though: it is reported as data
      not shown, with no figure or table behind it, whereas the N-terminal negative is
      reported as an outcome of a panel that is displayed - Figure 5a shows sensorgrams for
      the binders only, so the paper contains no ADAMTSL-1 trace for either half.
    supporting_text: >-
      Binding to the C-terminal half of fibrillin-1 was negative for all ADAMTSL proteins
      tested
    reference_section_type: RESULTS
  - statement: >-
      In the same study ADAMTSL-1 also failed to bind the non-catalytic C-terminal region of
      ADAMTS-10, which ADAMTSL-3 binds with high affinity. This result is corroborating rather
      than discriminating and must not be added to the fibrillin-1 one: ADAMTSL-2 is equally
      negative against ADAMTS-10 and still reaches GO:0030198, ADAMTS-10 binding was shown
      only for ADAMTSL-3, and ADAMTSL-6/THSD4 was never tested against it, so ADAMTS-10 is not
      what places ADAMTSL-2 or -6 in the fibrillin-1 pathway. The discriminating result is the
      fibrillin-1 negative alone.
    supporting_text: >-
      However, neither ADAMTSL-2 nor -1 bound to ADAMTS-10, indicating that ADAMTS enzymes may
      partner only with specific ADAMTSL proteins.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      The most informative molecular-function experiment ever performed on human ADAMTSL1, and
      it is a negative. Found only because a sibling review of ADAMTSL3 surfaced it: the paper
      is titled for fibrillin-1, so no ADAMTSL1-keyed search reaches it, and it is absent from
      ADAMTSL1's GOA and from the affinage record. One caveat travels with it, and it is the
      isoform question that runs through this whole review. The methods describe the reagent as
      "Recombinant full length ADAMTSL-1" but give no length, and in 2017 the Apte laboratory
      stated that no construct for the 1762-residue form existed. Both RefSeq entries were
      available in 2012 (NP_443098 for the 525-residue isoform 1, NP_001035362 for the
      1762-residue isoform 3), so the paper alone does not settle which was tested; the balance
      of evidence favours the short punctin-1 form. The negative is therefore firm for whatever
      was assayed and probably does not test the nine additional thrombospondin repeats, four
      Ig-like domains and PLAC domain of the long isoform. Recorded as a bounded negative
      rather than a blanket one.
- id: PMID:24634412
  title: Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926
    directly inhibits sarcoma cell growth.
  findings:
  - statement: >-
      ADAMTSL1 was identified as a Hedgehog-responsive gene in primary chondrosarcoma
      xenografts treated with the SMO inhibitor IPI-926, and manipulating it altered
      chondrosarcoma cell proliferation. This is the only gene-specific functional
      perturbation result reported for ADAMTSL1, and Apte is a co-author.
    supporting_text: >-
      Gene profiling studies identified genes differentially expressed in chondrosarcomas
      following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell
      proliferation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Adjudicated and deliberately not annotated, recorded here rather than only in the gene
      notes because it bears on this review's claim that ADAMTSL1 has no gene-specific
      functional data. Three reasons for declining. The cached record is abstract-only and the
      abstract does not state the direction of the effect, so neither GO:0008284 nor GO:0008285
      can be chosen and picking either would be a guess. The assay is a chondrosarcoma cell
      line in a Hedgehog-inhibitor study, a disease context with no normal-physiology
      counterpart for this gene. And a proliferation phenotype bears on neither of this
      review's recorded gaps, since it identifies no molecular function and says nothing about
      matrix organisation, so it narrows neither. It does mean the review's claim should be
      read precisely as no molecular function and no matrix-organisation evidence, rather than
      no functional observation of any kind.
- id: PMID:39880678
  title: Pmp2+ Schwann Cells Maintain the Survival of Large-Caliber Motor Axons.
  findings:
  - statement: >-
      Ablating the Schwann cell population co-marked by Adamtsl1, Cldn14 and Pmp2 causes loss
      of large-caliber motor axons. The perturbation is of the cell population, not of the
      gene, so the phenotype is a property of the cell type.
    supporting_text: >-
      Recently, we identified a population of Schwann cells (SCs) expressing Adamtsl1 ,
      Cldn14 , and Pmp2 (a.k.a. PMP2+ SCs) that preferentially myelinate large-caliber motor
      axons.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Not annotated, and recorded so that the decision is visible in the review file rather
      than only in the gene notes. Adamtsl1 is used only as one of three markers of the ablated
      population and the gene itself is never perturbed, so attributing the axonal phenotype to
      ADAMTSL1 would be a cell-level to gene-level projection error. Companion to
      PMID:35115729, which defined the subtype.
- id: file:human/ADAMTSL1/ADAMTSL1-uniprot.txt
  title: UniProtKB Q8N6G6 (ATL1_HUMAN) ADAMTS-like protein 1 record
  findings:
  - statement: >-
      The feature table over the 1762-residue precursor lists a signal peptide, nine
      annotated thrombospondin type-1 repeats, four Ig-like C2-type domains and a PLAC
      domain, with no metalloprotease domain, no disintegrin-like domain, no prodomain and no
      zinc-binding site. The entry states the absence explicitly and records no catalytic
      activity and no EC number.
    supporting_text: lacks the metalloprotease and disintegrin-like domains which are
  - statement: >-
      Despite that, the entry carries the molecular-function keyword Hydrolase (KW-0378),
      which is what generates the GO:0016787 hydrolase activity cross-reference in the
      entry's own GO list. This annotation is not present in GOA, because keyword-derived
      annotations were withdrawn for cellular organisms.
    supporting_text: 'Extracellular matrix; Glycoprotein; Hydrolase; Immunoglobulin domain;'
  - statement: >-
      The keyword-derived hydrolase activity term appears in the entry's own GO
      cross-reference block with evidence IEA:UniProtKB-KW.
    supporting_text: 'GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW.'
  - statement: >-
      The entry records that PAN-GO assigns no annotations to this protein from evolutionary
      models, consistent with the complete absence of IBA rows in GOA.
    supporting_text: 'PAN-GO; Q8N6G6; 0 GO annotations based on evolutionary models.'
  - statement: >-
      The ADAMTS spacer region named in the description is called by Pfam and InterPro rather
      than by a UniProt FT DOMAIN line, which is why it does not appear in the feature-table
      enumeration above.
    supporting_text: 'Pfam; PF05986; ADAMTS_spacer1; 1.'
  - statement: Tissue expression is highest in adult skeletal muscle.
    supporting_text: Expressed primarily in adult skeletal muscle.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Quotes taken from single physical lines of the flat file so that they survive the
      validator's whitespace normalisation across CC continuation lines.
- id: file:human/ADAMTSL1/ADAMTSL1-bioinformatics/RESULTS.md
  title: PTHR13723 annotation census for ADAMTSL1
  findings:
  - statement: >-
      Of the 26 human members of PANTHER family PTHR13723, 24 receive GO:0031012
      extracellular matrix by IBA from node PTN000347317. PAPLN does not, but holds the term
      from its own evidence. ADAMTSL1 is the only human member of the family with no
      GO:0031012 annotation from any evidence code, while its mouse orthologue - same
      subfamily SF157 - does receive the IBA from the same node.
    supporting_text: '**Members with no `GO:0031012` annotation of any kind: ADAMTSL1.**'
  - statement: >-
      Within the ADAMTS-like branch, ADAMTSL1 and THSD4 carry the Hydrolase keyword while
      ADAMTSL2, ADAMTSL3, ADAMTSL4 and ADAMTSL5 do not, and none of the six has a catalytic
      activity comment.
    supporting_text: 'Entries with a CATALYTIC ACTIVITY comment: none.'
  - statement: >-
      PAINT records IKR and IRD loss calls at node PTN002673039 that block metalloendopeptidase
      activity and proteolysis from propagating down the ADAMTS-like branch, but in GOA the
      loss reaches only ADAMTSL2. ADAMTSL1 receives neither the catalytic terms nor the
      negation.
    supporting_text: >-
      So the loss call is recorded for part of the branch and simply absent for the rest -
      ADAMTSL1 inherits neither the catalytic terms nor the statement that they do not apply.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Generated by check_family_propagation.py in the same directory from live QuickGO and
      UniProt plus the repo's cached PANTHER files. Two consecutive runs reproduce the file
      byte for byte, and the script's guards were exercised by deliberately corrupting each
      cached input and confirming it aborts rather than emitting a stale sentence.
- id: file:interpro/panther/PTHR13723/PTHR13723-paint.tsv
  title: PANTHER PTHR13723 PAINT node annotations
  findings:
  - statement: >-
      PAINT records an inferred-from-key-residues loss of metalloendopeptidase activity at
      node PTN002673039, negating the term that the family node PTN000347317 carries. A
      companion inferred-from-rapid-divergence row does the same for proteolysis.
    supporting_text: PTHR13723 PTN002673039 GO:0004222 F IKR true PANTHER:PTN000347317
  - statement: >-
      The family node PTN000347317 carries GO:0031012 extracellular matrix as an IBD
      annotation, which is the source of the IBA rows that 24 of 26 human family members
      receive and ADAMTSL1 does not.
    supporting_text: PTHR13723 PTN000347317 GO:0031012 C IBD false
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Repo-cached PAINT export for the family. Used for the node-level term placement, which
      is not visible from the per-gene GOA rows.
- id: file:human/ADAMTSL1/ADAMTSL1-deep-research-affinage.md
  title: Affinage mechanistic annotation for ADAMTSL1 (human)
  findings:
  - statement: >-
      The provider record passed its own gates (gates_passed True, faith 100 percent, ten
      numeric PMIDs, no preprint identifiers in PMID-shaped fields) and its central framing -
      a secreted matrix glycoprotein without the catalytic domains, with no demonstrated
      enzymatic activity - agrees with UniProt and with the primary literature.
    supporting_text: >-
      Direct biochemical demonstration of an enzymatic activity for the mammalian protein has
      not been established in the available corpus.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Used as a lead only. Every claim taken forward was re-verified against the cited PMID
      or against UniProt. Two divergences were found and are recorded in the gene notes: the
      record describes the protein as having four thrombospondin repeats, which is true of
      the short punctin-1 splice form but not of the 1762-residue canonical sequence, and it
      restates PMID:30714143's aggrecan mechanism in a softened form that the source paper
      does not use.
existing_annotations:
- term:
    id: GO:0030198
    label: extracellular matrix organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  supporting_entities:
  - InterPro:IPR013273
  review:
    summary: >-
      Family-signature inference that is correctly constructed and carries independent
      positive support at family level, but no ADAMTSL1 evidence. Kept, and explicitly not
      asserted as this gene's demonstrated core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Three things give this IEA positive support rather than merely leaving it unrefuted.
      First, the mapping is careful: IPR013273 (ADAMTS/ADAMTS-like) is the only one of
      ADAMTSL1's fourteen InterPro entries with any GO mapping, and it maps to GO:0030198
      alone - no peptidase, protease or hydrolase term - even though the signature also
      matches the catalytic ADAMTS metalloproteases. Second, GO:0030198 does not depend on the
      domain ADAMTSL1 lacks: catalytic family members reach the term through proteolysis, but
      ADAMTSL2, ADAMTSL4 and THSD4 reach it non-catalytically through fibrillin microfibril
      assembly, so the term sits at the level of generality at which a mechanistically
      heterogeneous family genuinely agrees, and a non-catalytic route to it is available to
      this architecture in principle. This ground has to be qualified for ADAMTSL1 in
      particular, and the qualification is a measured negative rather than an absence: in the
      one experiment that tested it, recombinant human ADAMTSL-1 did not bind the N-terminal
      half of fibrillin-1 in the same SPR panel in which ADAMTSL-2, ADAMTSL-3 and papilin did
      - and the same experiments report the C-terminal half negative for every ADAMTSL tested,
      albeit as data not shown, so the exclusion covers fibrillin-1 entire - and it did not
      bind the non-catalytic region of ADAMTS-10 either. Only the fibrillin-1 half of that is
      discriminating, and the two must not be double-counted: ADAMTSL-2 is equally negative
      against ADAMTS-10 and still reaches GO:0030198, ADAMTS-10 binding was shown only for
      ADAMTSL-3, and THSD4 was never tested against it. The load-bearing result is the
      fibrillin-1 negative alone, and it is sufficient: the specific route by which the
      relatives reach this term is excluded for ADAMTSL1. That does not refute GO:0030198,
      which is far broader than fibrillin-1 binding, but it removes the strongest mechanistic
      analogy and it is a further reason the term cannot be treated as core here. Third, PAINT
      arrived at the same term independently: GO:0030198 is an IBD annotation at PTN000347317,
      seeded by fourteen gene sources (eleven mouse, two fly, one nematode), and that node
      sits above ADAMTSL1. That last step is what makes this ground bear on the gene rather
      than merely on its family, so it is worth stating how it is established: mouse Adamtsl1
      is in PANTHER subfamily SF157, the same subfamily as human ADAMTSL1, and it receives the
      GO:0031012 IBA from PTN000347317, so that node is an ancestor of SF157 and therefore of
      ADAMTSL1. All three are family-level, and that is the limit of the case. What the
      annotation does not have is any ADAMTSL1 evidence. The laboratory that discovered the
      protein states that its tissue function is unknown and that matrix assembly and turnover
      is an expectation drawn from relatives; being resident in the matrix and being an MMP10
      substrate places ADAMTSL1 within matrix remodelling but does not show that it organises
      the matrix. Hence KEEP_AS_NON_CORE rather than ACCEPT, since ACCEPT would assert this as
      the gene's core function and the evidence does not reach that. Not
      MARK_AS_OVER_ANNOTATED either, on the three grounds above. The concurrent ADAMTSL5
      review marks its identical InterPro IEA MARK_AS_OVER_ANNOTATED; the two genes are in the
      same IBA position for this term, because neither receives the GO:0030198 IBA from
      PTN000347317 that ADAMTSL2, ADAMTSL4 and THSD4 do (computed in the bioinformatics
      census, section 1). They are no longer in the same evidentiary position overall, and the
      difference now runs against this review rather than for it: ADAMTSL5 has its own IDA to
      GO:0031012 plus microfibril and heparin binding, while ADAMTSL1 has a measured negative
      against the very route by which the family reaches GO:0030198, so the better-supported
      gene is the one taking the harsher action. That is an argument for settling the line
      family-wide rather than a reason to change one gene in isolation, so it is carried into
      suggested_questions rather than resolved here.
    supported_by:
    - reference_id: PMID:28722276
      supporting_text: >-
        The function of punctin-1 in tissues is currently unknown, however, by analogy with
        other family members (Apte 2009; Dubail and Apte 2015; Hubmacher and Apte 2015),
        there is a strong possibility that it mediates the assembly and turnover of
        extracellular matrix at the affected sites.
    - reference_id: PMID:24281761
      supporting_text: >-
        we identified the extracellular matrix protein ADAMTS-like protein 1 (ADAMTSL1) as a
        direct MMP10 substrate
    - reference_id: file:human/ADAMTSL1/ADAMTSL1-bioinformatics/RESULTS.md
      supporting_text: 'Entries with a CATALYTIC ACTIVITY comment: none.'
    - reference_id: file:human/ADAMTSL1/ADAMTSL1-deep-research-affinage.md
      supporting_text: >-
        Direct biochemical demonstration of an enzymatic activity for the mammalian protein
        has not been established in the available corpus.
    - reference_id: file:interpro/panther/PTHR13723/PTHR13723-paint.tsv
      supporting_text: PTHR13723 PTN000347317 GO:0030198 P IBD false
    - reference_id: PMID:22242013
      supporting_text: >-
        ADAMTSL-2, -3, and papilin polypeptides interacted with the N-terminal half of
        fibrillin-1, while ADAMTSL-1 did not.
    knowledge_gaps:
    - gap_statement: >-
        Whether ADAMTSL1 itself participates in organising the extracellular matrix, as
        opposed to merely residing in it and being turned over within it, has never been
        tested.
      boundary: >-
        Firmly established: ADAMTSL1 is secreted, is deposited punctately into the
        pericellular matrix, and is cleaved there by MMP10. Also established: three other
        members of its family regulate fibrillin microfibril assembly without catalysis, so a
        non-catalytic matrix-organising role is mechanistically available to this architecture
        in principle. Excluded for ADAMTSL1, however, is the specific route the relatives
        take: recombinant human ADAMTSL-1 did not bind the N-terminal half of fibrillin-1 in
        the SPR panel where ADAMTSL-2, ADAMTSL-3 and papilin did, and the same experiments
        found binding to the C-terminal half negative for every ADAMTSL tested, so the
        negative covers fibrillin-1 entire rather than one half of it - though that second
        half is reported as data not shown, with no figure or table behind it, whereas the
        N-terminal negative is reported as an outcome of a panel that is displayed. Figure 5a
        shows sensorgrams for the binders only, so the paper contains no ADAMTSL-1 trace for
        either half (PMID:22242013, subject to that study leaving its construct's isoform
        unstated). That excludes the route, not the process, which is why the row is kept
        rather than marked over-annotated. Not established: any ADAMTSL1 loss-of-function or
        assembly result bearing on matrix organisation, and no validated binding partner -
        FBN2 appears in affinity-purification data but has never been confirmed by an
        orthogonal assay.
      gap_kind:
      - BIOLOGY
      dark_aspect: BP_DARK
      status: OPEN
      significance: >-
        GO:0030198 is the gene's only functional annotation, and every downstream use of
        ADAMTSL1 as a matrix-organising protein rests on it. Testing it would either convert
        the family inference into a gene-specific fact or show that the prototype of the
        family does something else.
      resolution: >-
        A microfibril or matrix-assembly assay using recombinant full-length ADAMTSL1,
        together with matrix phenotyping of an Adamtsl1-null mouse, would settle it. Both
        have been blocked in practice by the absence of a full-length expression construct.
      provenance:
      - reference_id: PMID:28722276
        supporting_text: >-
          The function of punctin-1 in tissues is currently unknown, however, by analogy with
          other family members (Apte 2009; Dubail and Apte 2015; Hubmacher and Apte 2015),
          there is a strong possibility that it mediates the assembly and turnover of
          extracellular matrix at the affected sites.
      - reference_id: PMID:28722276
        supporting_text: A plasmid construct for full-length ADAMTSL1 is presently unavailable.
      - reference_id: PMID:22242013
        supporting_text: >-
          ADAMTSL-2, -3, and papilin polypeptides interacted with the N-terminal half of
          fibrillin-1, while ADAMTSL-1 did not.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5173005
  qualifier: located_in
  review:
    summary: >-
      True but non-core. ADAMTSL1's thrombospondin repeats really are glucosylated by B3GLCT
      in the ER lumen, so the protein occupies that compartment during biosynthesis; it acts
      in the extracellular matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      The underlying biology is experimentally supported for this gene rather than inferred
      from pathway membership alone: mass spectrometry of punctin-1 detected the
      fucose-glucose disaccharide that B3GLCT produces on TSR2, TSR3 and TSR4, and mutating
      the modified residues reduces secretion. The compartment assignment is therefore
      correct. It is marked non-core because the endoplasmic reticulum lumen is a
      biosynthetic transit compartment for a secreted protein, not its site of action, and
      because the Reactome pipeline projects the compartment of a reaction's participant set:
      this reference annotates about nine gene products with the same three terms, so it is
      one statement about set membership rather than an observation about ADAMTSL1.
    supported_by:
    - reference_id: PMID:17395588
      supporting_text: >-
        Mutation of the putative modified Ser/Thr residues in TSR2, TSR3, and TSR4 led to
        significantly decreased levels of secreted punctin-1.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5173192
  qualifier: located_in
  review:
    summary: >-
      Same statement as the B3GLCT row, from the upstream reaction of the same pathway.
      POFUT2 acts on ADAMTSL1's thrombospondin repeats in the ER lumen; kept as a transit
      location rather than a functional one.
    action: KEEP_AS_NON_CORE
    reason: >-
      POFUT2 is the ER-resident enzyme that installs the O-fucose on which B3GLCT builds, and
      ADAMTSL1 is a demonstrated substrate: the O-fucose was mapped to Thr48, Thr312, Ser391
      and Thr451 by mass spectrometry, and C-mannosylation of the adjacent tryptophans in the
      same repeat was mapped in the companion study, with both modifications acting together
      as a gate on export. The compartment is correct and better supported than the other two
      rows, but it remains a biosynthetic transit compartment rather than the site where the
      protein functions. This is one of three GOA rows asserting the identical term for the
      same gene from three reactions of one Reactome pathway.
    supported_by:
    - reference_id: PMID:19671700
      supporting_text: >-
        Together, these modifications appear to provide a quality control mechanism for
        punctin-1 secretion.
    - reference_id: PMID:17395588
      supporting_text: >-
        the data define a critical role for N-glycosylation and O-fucosylation in the
        biosynthesis of punctin-1
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785565
  qualifier: located_in
  review:
    summary: >-
      The weakest of the three identical rows: it derives from a Reactome FailedReaction
      modelling the Peters-plus disease state, in which the B3GALTL G393E variant does not
      glucosylate its substrates. The location it asserts is still correct, but it carries no
      information the two working reactions do not already supply.
    action: KEEP_AS_NON_CORE
    reason: >-
      Verified against the Reactome content service: R-HSA-6785565 has schemaClass
      FailedReaction, its catalyst is the B3GALTL G393E disease variant, and it has inputs but
      no outputs. The GO pipeline emits the compartment of the input participant set
      regardless of whether the reaction proceeds, so ADAMTSL1 receives the same endoplasmic
      reticulum lumen assignment it already has from R-HSA-5173005. Kept because the
      compartment claim is not wrong and ADAMTSL1 is a genuine B3GLCT substrate, but marked
      non-core on the same transit-compartment grounds as its two siblings, and flagged as
      redundant. Whether a FailedReaction should emit a location annotation identical to that
      of the corresponding working reaction is raised as a question for the Reactome-GO
      pipeline rather than treated as a defect in this gene's record.
    supported_by:
    - reference_id: PMID:17395588
      supporting_text: >-
        Mutation of the putative modified Ser/Thr residues in TSR2, TSR3, and TSR4 led to
        significantly decreased levels of secreted punctin-1.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IDA
  original_reference_id: PMID:11805097
  qualifier: located_in
  isoform: Q8N6G6-1
  review:
    summary: >-
      Proposed new annotation. ADAMTSL1 is the only one of the 26 human members of PANTHER
      family PTHR13723 with no extracellular matrix annotation of any kind, even though its
      matrix deposition is directly observed in human cells, endogenous untagged protein is
      recovered from human fibroblast secretomes (PMID:24281761), and its mouse orthologue
      receives the term by IBA from the same PANTHER node.
    action: NEW
    reason: >-
      The gap was found by census rather than by inspection. PAINT holds GO:0031012 as an IBD
      annotation at node PTN000347317; 24 of the 26 human members of PTHR13723 receive it by
      IBA from that node, and the one further exception, PAPLN, holds the term from its own
      evidence, which is the expected behaviour since PAINT does not lay an IBA over a direct
      annotation. ADAMTSL1 has neither. The gap is species-specific rather than
      subfamily-specific: mouse Adamtsl1 (Q8BLI0), the same PANTHER subfamily SF157, does
      receive the IBA from PTN000347317 and additionally carries three HDA rows from matrisome
      proteomics. Human evidence is not lacking. UniProt records the location as supported by
      three experimental references, the founding paper shows recombinant punctin deposited
      punctately into the cell substratum and excluded from focal contacts, and endogenous
      untagged ADAMTSL1 was recovered from human fibroblast secretomes and named as a direct
      MMP10 substrate. The caveat on the primary evidence is that the 2002 assay used
      epitope-tagged protein in a heterologous cell line, which is why the secretome result is
      cited alongside it: it is native protein in a primary human cell type, and it is
      independent of the tag. The isoform field records that the assayed material was the
      525-residue punctin-1 form, which is what was purified and expressed; it is not a claim
      that the localisation is restricted to that isoform, and it should not be read as one.
      Isoforms 1 to 4 all retain the signal peptide, so all are expected to be secreted, while
      isoforms 5 and 6 delete it and would not be.
    additional_reference_ids:
    - PMID:24281761
    - PMID:17395588
    supported_by:
    - reference_id: PMID:11805097
      supporting_text: >-
        In transfected COS-1 cells, punctin is deposited in the cell substratum in a punctate
        fashion and is excluded from focal contacts.
    - reference_id: PMID:24281761
      supporting_text: >-
        we identified the extracellular matrix protein ADAMTS-like protein 1 (ADAMTSL1) as a
        direct MMP10 substrate
    - reference_id: file:human/ADAMTSL1/ADAMTSL1-bioinformatics/RESULTS.md
      supporting_text: '**Members with no `GO:0031012` annotation of any kind: ADAMTSL1.**'
    - reference_id: file:interpro/panther/PTHR13723/PTHR13723-paint.tsv
      supporting_text: PTHR13723 PTN000347317 GO:0031012 C IBD false
core_functions:
- description: >-
    A secreted, heavily glycosylated ADAMTS-like protein deposited into the pericellular
    matrix. The location is the only part of this that the gene's own data establishes, so it
    is the only structured claim made here. No molecular function, ligand or binding partner
    has been identified, so no molecular-function term is asserted; and although the gene
    carries GO:0030198 extracellular matrix organization from the family InterPro signature,
    that term has no ADAMTSL1-specific support, so it is deliberately not repeated as a core
    process here and is instead reviewed on its own row as KEEP_AS_NON_CORE, where its family-
    level basis and the limits of that basis are set out. What can be said positively about
    the protein's role in matrix remodelling is negative in form: it is a substrate of
    extracellular proteolysis rather than an agent of it, having none of the catalytic
    machinery of the ADAMTS proteases and being itself cleaved by MMP10 in fibroblast
    secretomes.
  locations:
  - id: GO:0031012
    label: extracellular matrix
  supported_by:
  - reference_id: PMID:11805097
    supporting_text: >-
      In transfected COS-1 cells, punctin is deposited in the cell substratum in a punctate
      fashion and is excluded from focal contacts.
  - reference_id: PMID:24281761
    supporting_text: >-
      we identified the extracellular matrix protein ADAMTS-like protein 1 (ADAMTSL1) as a
      direct MMP10 substrate
  - reference_id: PMID:28722276
    supporting_text: >-
      it also contains a family of seven ADAMTS-like proteins (ADAMTSL family) comprising an
      ADAMTS ancillary domain but lacking the protease domain and thus, enzymatic activity
knowledge_gaps:
- gap_statement: >-
    No molecular function is known for ADAMTSL1: no ligand, no binding partner, no activity
    and no structural role has been demonstrated, and the gene carries no molecular-function
    annotation of any evidence code in GOA.
  boundary: >-
    Well established: the protein's domain content (thrombospondin type-1 repeats, four Ig-
    like C2-type domains, ADAMTS spacer, PLAC domain, no catalytic domains), its secretion and
    matrix deposition, the glycosylation chemistry that gates its export, its cleavage by
    MMP10, and a dominant-negative human allele. Also now bounded on the other side by
    measured negatives rather than by silence: recombinant human ADAMTSL-1 did not bind the
    N-terminal half of fibrillin-1 in an SPR panel where ADAMTSL-2, ADAMTSL-3 and papilin did,
    and the same experiments report the C-terminal half negative for every ADAMTSL tested,
    which is what licenses stating the exclusion as fibrillin-1 binding rather than N-terminal
    fibrillin-1 binding, though that second half is given as data not shown. ADAMTSL-1 also
    did not bind the non-catalytic region of ADAMTS-10. Only the fibrillin-1 result
    discriminates ADAMTSL1 from its relatives - ADAMTSL-2 is equally negative against
    ADAMTS-10 and ADAMTSL-6/THSD4 was never tested against it - so what is excluded is
    fibrillin-1 binding, with the ADAMTS-10 result corroborating rather than adding to it, and
    both subject to the caveat that the construct's isoform is not stated. Entirely open: what
    the protein does bind, and what it does once it is in the matrix.
  gap_kind:
  - BIOLOGY
  dark_aspect: MF_DARK
  status: OPEN
  significance: >-
    ADAMTSL1 is the prototype of the ADAMTS-like family and is implicated in a multisystem
    developmental disorder, yet has no molecular handle at all. Until a partner is identified
    the disease mechanism cannot be modelled beyond loss of secretion, and the family-level
    extracellular matrix organization inference cannot be made specific.
  resolution: >-
    Identification of a physical binding partner for recombinant full-length ADAMTSL1 would
    supply the first molecular-function term. The obvious family candidates are now poorer
    candidates than they look: fibrillin-1 and ADAMTS-10 were both tested by SPR in
    PMID:22242013 and both were negative, so an unbiased search is more appropriate than
    another fibrillin-1 experiment. Fibrillin-2 is not reported as tested anywhere, and FBN2
    appears among the affinity-purification hits, so it is the one family-shaped hypothesis
    still standing. No LTBP result for ADAMTSL1 appears in the main text of PMID:22242013
    either, but LTBP-1 and LTBP-4 were coupled to chips in the same experiments and the LTBP
    data sit in a supplementary table absent from the cached record, so untested is not a safe
    reading for those. Producing a construct for the 1762-residue form is the prerequisite for
    all of it, and would also determine whether the published negatives extend to the long
    isoform.
  provenance:
  - reference_id: PMID:28722276
    supporting_text: >-
      The function of punctin-1 in tissues is currently unknown, however, by analogy with
      other family members (Apte 2009; Dubail and Apte 2015; Hubmacher and Apte 2015), there
      is a strong possibility that it mediates the assembly and turnover of extracellular
      matrix at the affected sites.
  - reference_id: PMID:22014523
    supporting_text: >-
      The biological role of MADD-4 orthologs, including ADAMTSL1 and 3 in mammals, is
      unknown.
  - reference_id: PMID:22242013
    supporting_text: >-
      However, neither ADAMTSL-2 nor -1 bound to ADAMTS-10, indicating that ADAMTS enzymes
      may partner only with specific ADAMTSL proteins.
suggested_questions:
- question: >-
    Where should the family draw the line between KEEP_AS_NON_CORE and MARK_AS_OVER_ANNOTATED
    for the InterPro GO:0030198 IEA that every ADAMTS-like protein carries? ADAMTSL1 and
    ADAMTSL5 are in the same IBA position for this term: both hold the IPR013273 IEA, and
    neither receives the GO:0030198 IBA from PTN000347317 that ADAMTSL2, ADAMTSL4 and THSD4
    do. Their wider evidence now differs, and in the direction that cuts against this review:
    ADAMTSL5 has its own IDA to GO:0031012 plus microfibril and heparin binding, while
    ADAMTSL1 has a measured SPR negative against fibrillin-1, the route by which the family
    reaches GO:0030198. The better-supported gene is thus the one taking the harsher action,
    which is an argument for settling the line family-wide rather than a tie to be broken per
    gene. The concurrent ADAMTSL5 review marks the row MARK_AS_OVER_ANNOTATED; this review
    marks it KEEP_AS_NON_CORE, on the grounds that the term is the level of generality at
    which the heterogeneous family agrees, that PAINT independently placed it as an IBD at a
    node covering both genes, and that a non-catalytic route to it is demonstrably available
    to this architecture. The difference between the genes is therefore real but points the
    wrong way to explain the divergence: it would justify the harsher action on ADAMTSL1, not
    the milder one, so it cannot be what separates the two verdicts. The line should be
    settled once for the family rather than gene by gene.
  experts:
  - GO Central / PAN-GO curators
- question: >-
    Should the molecular-function keyword Hydrolase (KW-0378) be removed from Q8N6G6? It
    generates the GO:0016787 hydrolase activity cross-reference in the entry's own GO list,
    while the same entry's CAUTION comment states that the metalloprotease and
    disintegrin-like domains are absent, and there is no CATALYTIC ACTIVITY comment, no EC
    number and no active-site or metal-binding feature. Of the six human ADAMTS-like
    proteins, only ADAMTSL1 and THSD4 carry the keyword; ADAMTSL2, ADAMTSL3, ADAMTSL4 and
    ADAMTSL5 carry the identical CAUTION and no molecular-function keyword. Should THSD4
    (Q6ZMP0), which carries the keyword but has no CAUTION comment at all, be reviewed at the
    same time? The annotation no longer reaches GOA, since keyword-derived annotations were
    withdrawn for cellular organisms, so this is a defect that is live in UniProt and
    invisible in GO.
  experts:
  - UniProt curators
- question: >-
    Why does human ADAMTSL1 carry no GO:0031012 extracellular matrix annotation at all, when
    the term is an IBD at node PTN000347317, 24 of the 26 human members of PTHR13723 receive
    it by IBA from that node, and mouse Adamtsl1 in the same subfamily SF157 does receive it
    from the same node? Two human members miss the IBA. PAPLN is the other, and its case is
    not explained by PAINT declining to overlay an existing direct annotation, because its
    only GO:0031012 rows are IEA and TAS, neither experimental; the concurrent ADAMTSL5 review
    sharpens that further by showing three PAPLN orthologs are themselves seeds at the node.
    ADAMTSL1 is the one that ends up with no annotation at all. Both look like propagation
    coverage gaps rather than curatorial decisions, and in ADAMTSL1's case the gap has landed
    on the family member whose matrix deposition is directly observed in human cells.
  experts:
  - GO Central / PAINT curators
- question: >-
    Should PAINT's loss calls at node PTN002673039 propagate to the other ADAMTS-like
    members? The node carries an inferred-from-key-residues loss of GO:0004222
    metalloendopeptidase activity and an inferred-from-rapid-divergence loss of GO:0006508
    proteolysis, correctly recording that catalysis was lost on this branch, but in GOA that
    judgement surfaces as exactly one annotation, ADAMTSL2's negated GO:0004222 row. For
    ADAMTSL1 the negated annotation would be the machine-readable form of a statement UniProt
    already makes in prose, and it would inoculate the gene against the recurring
    reappearance of proteolytic activity in family-level summaries.
  experts:
  - GO Central / PAINT curators
- question: >-
    Should the PANTHER family GO-slim and protein-class view be made aware of PAINT's own
    loss calls? The geneinfo service returns GO_SLIM_MF GO:0004222 metalloendopeptidase
    activity, GO_SLIM_BP GO:0006508 proteolysis and protein class PC00153 metalloprotease for
    every member of PTHR13723 queried, including all six ADAMTS-like proteins and including
    ADAMTSL2, whose GOA record explicitly negates GO:0004222, so a non-catalytic member is
    summarised as a metalloprotease.
  experts:
  - PANTHER curators
- question: >-
    What action should a review record for a biosynthetic-transit compartment row? ADAMTSL1
    and ADAMTSL4 carry the identical three GO:0005788 TAS rows from the same three Reactome
    reactions; the merged ADAMTSL4 review records them as ACCEPT while its reason describes
    them as reflecting secretory pathway transit rather than a functional localisation, and
    this review records the same judgement as KEEP_AS_NON_CORE. A convention would remove the
    discrepancy in either direction.
  experts: []
- question: >-
    Should Reactome FailedReactions contribute location annotations to GO? R-HSA-6785565
    models a disease state in which glucosylation does not occur, yet it emits a GO:0005788
    location annotation identical to the one from the corresponding working reaction
    R-HSA-5173005, adding a third identical row here without adding information.
  experts:
  - Reactome curators
- question: >-
    What does ADAMTSL1 bind, given that the obvious family candidates are already excluded?
    Unlike ADAMTSL2, ADAMTSL3, THSD4 and papilin, recombinant human ADAMTSL-1 did not bind the
    N-terminal half of fibrillin-1, and it did not bind the non-catalytic region of ADAMTS-10
    either, in the same study. Two questions follow. Does the negative extend to the
    1762-residue isoform, since the paper describes its reagent only as full length and the
    group that made the protein stated in 2017 that no long-form construct existed? And if
    ADAMTSL1 is genuinely outside the fibrillin-1 pathway that unites the rest of the family,
    what does the prototype of the ADAMTS-like family actually do? FBN2 appears among its
    affinity-purification hits and fibrillin-2 has not been tested, which is the one family-
    shaped hypothesis still standing.
  experts:
  - Suneel S. Apte
  - Dirk Hubmacher
suggested_experiments:
- hypothesis: >-
    The nine thrombospondin repeats, four immunoglobulin-like domains and PLAC domain that
    are absent from punctin-1 carry functions that no published experiment has been able to
    test.
  description: >-
    Build a full-length ADAMTSL1 expression construct and purify the 1762-residue protein.
    This is the rate-limiting step for everything else: the 2017 study states that no such
    construct existed, so every published biochemical result is confined to the 525-residue
    punctin-1 splice form.
  experiment_type: recombinant protein expression
- hypothesis: >-
    ADAMTSL1 has a matrix binding partner outside the fibrillin-1 / ADAMTS-10 axis that unites
    the rest of the ADAMTS-like family.
  description: >-
    An unbiased partner search rather than another candidate test: pull-down or proximity-
    labelling from a matrix-producing human cell line using recombinant full-length ADAMTSL1
    as bait, with mass-spectrometric identification. Candidate SPR should be reserved for
    fibrillin-2 and heparin, which are not reported as tested anywhere, and for LTBP1 and
    LTBP4, whose ADAMTSL1 results are absent from that study's main text but may sit in a
    supplementary table not present in the cached record and are worth checking before
    assaying. Use ADAMTSL2 or ADAMTSL3 as the positive control. Fibrillin-1 and the non-
    catalytic region of ADAMTS-10 should be included only as controls, since recombinant human
    ADAMTSL-1 has already been shown not to bind either, and repeating them with the
    1762-residue isoform would additionally test whether that published negative extends to
    the long form.
  experiment_type: protein-protein interaction assay
- hypothesis: >-
    ADAMTSL1 promotes or restrains fibrillin microfibril deposition, which would make
    GO:0030198 a gene-specific rather than a family-level annotation.
  description: >-
    Assay fibrillin microfibril deposition in fibroblast cultures with ADAMTSL1 knocked down
    or supplemented with recombinant protein, the standard test used to establish the
    matrix-organising role of the other ADAMTS-like proteins.
  experiment_type: cell-based matrix assembly assay
- hypothesis: >-
    The peripheral-nerve phenotype attributed to Pmp2-positive Schwann cells is a property of
    that cell population rather than of Adamtsl1, which is only one of its markers.
  description: >-
    Phenotype an Adamtsl1-null mouse for the tissues where the human phenotype localises -
    ocular anterior segment and intraocular pressure, mandibular condylar cartilage,
    dentition, and skeletal muscle - and compare the peripheral-nerve phenotype directly with
    that of Pmp2-positive Schwann cell ablation.
  experiment_type: mouse knockout phenotyping
- hypothesis: >-
    ADAMTSL1 acts through an MMP10-generated fragment rather than as an intact protein.
  description: >-
    Map the MMP10 cleavage site in ADAMTSL1 and test whether the released fragment has
    activity of its own, since a matrix protein whose only reported enzymatic relationship is
    being a substrate may be functioning through a processed form.
  experiment_type: degradomics and fragment activity assay
- hypothesis: >-
    Native ADAMTSL1 occupies the extracellular matrix of the tissues where its loss produces
    disease, not only that of transfected cells in culture.
  description: >-
    Localise endogenous ADAMTSL1 protein, not transcript, in adult human skeletal muscle and
    in the ocular anterior segment. All existing localisation data come from recombinant
    protein in transfected cells or from secretome proteomics, so an antibody-based
    localisation in the affected tissues would put the extracellular matrix annotation on
    native protein in its own tissue context.
  experiment_type: immunohistochemistry

ADAMTSL1

Gene Description

Functional Isoforms

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Knowledge Gaps

Deep Research

Affinage

Affinage mechanistic annotation for ADAMTSL1 (human)

Current model (mechanistic narrative)

Affinage mechanism profile (its own GO/Reactome grounding)

Dated findings (citation-anchored)

Citations

📚 Additional Documentation

Notes

ADAMTSL1 (Q8N6G6, punctin-1) — review notes

1. Domain content: the "-like" really does mean non-catalytic

2. The peptidase error IS present — but in UniProt's keywords, not in GOA

3. PAINT knows catalysis was lost on this branch, and says so on one gene out of six

4. The headline finding: ADAMTSL1 is the only human family member with no GO:0031012

5. GO:0030198 extracellular matrix organization (the one IEA)

Divergence from the concurrent ADAMTSL5 review, and a premise that turned out false

6. The GO:0005788 ER lumen rows (three of them)

7. Isoforms — the short form is punctin-1, not the long one

8. Checks run, including the ones that came back negative

8b. The one molecular-function experiment ever done on ADAMTSL1, and it is negative

8c. A gap in checkquotes.py worth knowing about

8d. The recurring defect in this review, and what finally caught it

9. What ADAMTSL1 is, in one paragraph

Bioinformatics Results

PTHR13723 annotation census for ADAMTSL1

1. GO:0031012 coverage across human PTHR13723

GO:0030198 coverage, same node

2. Hydrolase keyword across the ADAMTS-like branch

3. PAINT's own loss calls in this family

4. IBD seed composition at the family node

Guards

📄 View Raw YAML

4. The headline finding: ADAMTSL1 is the only human family member with no `GO:0031012`

5. `GO:0030198` extracellular matrix organization (the one IEA)

6. The `GO:0005788` ER lumen rows (three of them)

8c. A gap in `checkquotes.py` worth knowing about

1. `GO:0031012` coverage across human PTHR13723

`GO:0030198` coverage, same node

2. `Hydrolase` keyword across the ADAMTS-like branch