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.
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.
| 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 |