DNAAF11

Summary: Retain impaired ciliary movement as a physiological consequence of defective dynein arms.

Reason: The human patient study measures impaired respiratory ciliary beating and absent or reduced outer and inner arms. DNAAF11 contributes to assembly rather than acting as the force-generating motor. Preserve the valid movement annotation while the core specifies arm assembly.

Summary: Retain the ortholog-supported mucociliary fluid-movement role.

Reason: The mouse donor O88978 has an experimentally established motile-cilia defect, and human airway disease and ciliary-beating assays corroborate the biological function. This is a tissue-level outcome of dynein assembly. The cited ISS source is preserved; no direct human fluid-flow measurement is attributed to that transfer.

Summary: Retain the experimentally supported ZMYND10 association with its construct limits.

Reason: The original reports tagged human LRRC6–ZMYND10 co-immunoprecipitation, rat-lysate pull-downs and interaction of the LRRC6 CS region with ZMYND10. This supports an assembly-factor interaction. ZMYND10 is a co-chaperone, not a demonstrated autonomous protein-folding chaperone; binding it does not establish LRRC6 folding, motor or enzyme activity. No more informative molecular-function class is securely assigned to this association.

Summary: Retain the human LRRC6–ZMYND10 interaction.

Reason: The separately recovered primary Methods/Results excerpt describes human cDNAs in yeast two-hybrid assays and GST-ZMYND10 pull-down of in-vitro-translated Myc-LRRC6, with GST control. It supports binding capacity, while the mechanistic contribution of the pair to folding remains unresolved. The normal cache is abstract-only; the original excerpt is documented separately. No autonomous chaperone activity is inferred.

Summary: Retain the SCRIB association detected by affinity purification.

Reason: The literal human Q86X45–Q14160 record (IntAct EBI-9394895) is anti-tag co-immunoprecipitation from HEK293T, with C-terminal FLAG-tagged LRRC6. SCRIB is a polarity scaffold, but this experiment does not resolve a direct LRRC6–SCRIB interface or show that LRRC6 recognizes a cytoskeletal regulatory activity of SCRIB. Preserve the positive association without assigning scaffold, chaperone or polarity function to LRRC6.

Summary: Retain the ZMYND10 association and distinguish partner stabilization from LRRC6 chaperone activity.

Reason: The original combines mouse tissue interaction data with tagged-protein experiments in HEK293T cells. ZMYND10 increases LRRC6 stability in cycloheximide chases; that direction must not be inverted into a demonstrated LRRC6 protein-folding activity. A later study reproduces tagged association but fails to detect endogenous association in mouse testes under its conditions, suggesting context-dependent detection rather than disproving all positive assays.

Summary: Specify binding to the verified DEAD-box helicase partner DDX6.

Reason: The positive HuRI validated two-hybrid record EBI-24771467 joins the exact human LRRC6 and 483-residue DDX6 sequences. The DDX6 record contains the paired helicase domains and DEAD motif, supporting the DEAD-box partner class. GO:0017151 describes binding to that class, not RNA-helicase activity of LRRC6. Pooled, array and validated records are stages of one study; its main text describes quadruplicate retesting and sequence confirmation. The result supports qualitative binding capacity, without pair-specific orthogonal validation or demonstration of a native ciliary complex.

Proposed replacements: DEAD/H-box RNA helicase binding

Summary: Retain the verified HuRI interaction with TERF1 isoform 2 (P54274-2).

Reason: The exact sequence/taxon joins match the source proteins. Three records represent pooled screening, pairwise array testing and validated two-hybrid stages of the same study, including a positive MI:1356 result in yeast; they are not three independent studies. TERF1 binds telomeric DNA and also has spindle localization. Those roles are not transferred to LRRC6, and the screen does not resolve a telomeric or mitotic function of the interaction; no absolute compartment incompatibility is asserted. No native ciliary complex or pair-specific orthogonal validation is claimed.

Summary: Specify binding to the verified MEOX2 transcription-factor clone.

Reason: The positive HuRI validated two-hybrid record EBI-24407380 uses the literal 303-residue Q6FHY5 clone. Its sequence differs from reviewed MEOX2 P50222 only by deletion of canonical Q81, outside the intact homeobox. The reviewed MEOX2 record establishes DNA-dependent transcriptional activation, supporting classification of the tested clone as a DNA-binding transcription-factor partner; no clone-specific transcription assay is claimed. GO:0140297 describes that binding capacity without assigning transcriptional activity to LRRC6. Pooled, array and validated records are stages of one study, not independent studies or pair-specific orthogonal confirmation; a native LRRC6 transcriptional pathway remains unestablished.

Proposed replacements: DNA-binding transcription factor binding

Summary: Retain the verified HuRI interaction with TTC23L (Q6PF05).

Reason: The exact sequence/taxon joins match the source proteins. Three records represent pooled screening, pairwise array testing and validated two-hybrid stages of the same study, including a positive MI:1356 result in yeast; they are not three independent studies. TTC23L has centrosomal, spindle and midbody localization, but those locations and a TPR domain do not establish a particular ligand-binding class or an LRRC6-dependent cytoskeletal mechanism. No native ciliary complex or pair-specific orthogonal validation is claimed.

Summary: Retain the verified HuRI interaction with SSX7 (Q7RTT5).

Reason: The exact sequence/taxon joins match the source proteins. Three records represent pooled screening, pairwise array testing and validated two-hybrid stages of the same study, including a positive MI:1356 result in yeast; they are not three independent studies. The partner record only proposes transcription-modulatory activity. The assay does not establish a DNA-binding transcription-factor class or transcriptional role for this LRRC6 association. No native ciliary complex or pair-specific orthogonal validation is claimed.

Summary: Retain the verified HuRI interaction with podocan isoform 3 (Q7Z5L7-3).

Reason: The exact sequence/taxon joins match the source proteins. Three records represent pooled screening, pairwise array testing and validated two-hybrid stages of the same study, including a positive MI:1356 result in yeast; they are not three independent studies. This tested isoform is annotated as cytoplasmic, unlike secreted podocan isoform 1. A false extracellular-versus-cytoplasmic mismatch is therefore avoided. The screen nevertheless does not establish an extracellular-matrix-binding or other specialized physiological function for LRRC6. No native ciliary complex or pair-specific orthogonal validation is claimed.

Summary: Retain the verified HuRI interaction with LRCH3 isoform 3 (Q96II8-3).

Reason: The exact sequence/taxon joins identify the tested LRCH3 isoform 3, and a positive MI:1356 record accompanies the two HuRI screen stages. LRCH3 is associated with the DISP cytoskeletal regulatory complex, but its own curated activity is tentative rather than an established autonomous cytoskeletal-regulator function. Thus GO:0005519 would rest on an uncertain partner class. Retain the positive binding capacity without transferring complex activity to LRCH3 or LRRC6; no native ciliary complex or pair-specific orthogonal validation is claimed.

Summary: Retain the verified HuRI interaction with PLEKHF2 (Q9H8W4).

Reason: The exact sequence/taxon joins match the source proteins. Three records represent pooled screening, pairwise array testing and validated two-hybrid stages of the same study, including a positive MI:1356 result in yeast; they are not three independent studies. PLEKHF2 participates in endosome-associated trafficking. Binding capacity does not establish LRRC6 as a trafficking adaptor or receptor regulator; neither the partner localization nor its PH/FYVE domains supplies a more specific LRRC6 function. No native ciliary complex or pair-specific orthogonal validation is claimed.

Summary: Retain the verified HuRI interaction with LSM2 (Q9Y333).

Reason: The exact sequence/taxon joins match the source proteins. Three records represent pooled screening, pairwise array testing and validated two-hybrid stages of the same study, including a positive MI:1356 result in yeast; they are not three independent studies. LSM2 contributes to RNA-associated LSM complexes. Its complex membership does not establish that LRRC6 binds RNA, joins the spliceosome, or performs an RNA-processing function. The isolated protein pair remains useful non-core evidence. No native ciliary complex or pair-specific orthogonal validation is claimed.

Summary: Retain the independently detected SCRIB association.

Reason: The BioPlex record EBI-54631541 identifies human LRRC6 with SCRIB in HEK293T anti-tag affinity purification, using a C-terminal tandem tag on LRRC6. This corroborates the earlier association but remains a co-complex assay, not a resolved binary interface or evidence that LRRC6 performs SCRIB-related polarity regulation. The same conservative disposition is used for the earlier SCRIB source.

Summary: Reject the electronic extracellular-location inference.

Reason: The source is an electronic located_in assertion whose with/from fields are the extracellular-fluid-movement processes GO:0003351 and GO:0060287. Those processes describe fluid moved by cilia; they do not locate the assembly factor outside the plasma membrane. Direct human experiments place LRRC6 in cytoplasm and dynein-containing intracellular foci, with separate cell-type-dependent ciliary observations. Neither a membrane-enclosed cilium nor its effect on extracellular fluid establishes extracellular LRRC6. This is a source-role mismatch, not an inference from absence of a signal peptide.

Summary: Refine the conserved germ-cell cytoplasmic location without assigning it to DynAPs.

Reason: The recovered original PMID:33403504 Results and Figure 4 identify mouse germ-cell cytoplasm; Figure 2c separately concerns human patient/control sperm flagella. The gene-level cytoplasmic assignment is independently supported by human airway studies. Refine to the already accepted cytosol location using the independent O88978 MGI IDA records from PMID:27353389 in spermatocytes and spermatids. Those finer donor annotations remain curator-supported because that full original was not recovered. This does not claim that the Figure 4 images distinguish cytosol from every organelle or demonstrate germ-cell DynAPs. This target-level synthesis is not exhaustive coverage of every original cell’s cytoplasm.

Proposed replacements: cytosol

Summary: Retain the valid ancestral cytoplasmic location and specify two supported target locations.

Reason: The literal cytoplasm IBD at PTN007663797 lies on the Q86X45 lineage; target experimental grounding is legitimate, not circular. At the human gene level, the accepted mouse-to-human cytosol transfer and direct endogenous human airway DynAP imaging support two distinct locations. Refine the broad term to both without attributing DynAPs to the ancestral IBD or its entire clade. The O88978 cytosol records are independently curated from PMID:27353389; the DynAP evidence comes from PMID:30561330. Neither source establishes that every observed cytoplasmic pool occupies both compartments. This target-level synthesis is not exhaustive coverage of every original cell’s cytoplasm.

Proposed replacements: cytosol dynein axonemal particle

Summary: Preserve human nasal-cell cytoplasmic localization while distinguishing finer locations.

Reason: Control human nasal-brush cells show LRRC6 in the cytoplasm and cilia, with mutant loss supporting staining specificity. Preserve both observations. The integrated gene-level refinement includes cytosol, independently supported by curated O88978 donor records, and DynAPs, directly demonstrated by later endogenous human airway imaging. The original nasal-cell assay is not relabeled as a DynAP or soluble-fraction experiment, and the later foci do not eliminate other cytoplasmic pools. This target-level synthesis is not exhaustive coverage of every original cell’s cytoplasm.

Proposed replacements: cytosol dynein axonemal particle

Summary: Preserve distributed human cytoplasmic staining alongside later DynAP evidence.

Reason: The human airway study reports LRRC6 throughout the cytoplasm, proximal to basal bodies, with no axonemal signal in this preparation. That distributed observation remains valid. Refine the gene-level location to the independently curated cytosol assignment and the later directly demonstrated human airway DynAP location. The cytosol transfer is grounded in O88978 MGI annotations from PMID:27353389; the DynAP study is PMID:30561330. Neither the original distributed image nor the later punctate image is treated as proof that the other pool is absent. This target-level synthesis is not exhaustive coverage of every original cell’s cytoplasm.

Proposed replacements: cytosol dynein axonemal particle

Summary: Specify two independently supported locations without changing the electronic source.

Reason: The matching ARBA family/domain conditions, mouse orthology and UniProt cytoplasmic location support the broad source assignment. At the target-gene level, retain both finer locations: the already accepted cytosol transfer from O88978 and directly imaged DynAPs in human airway multiciliated cells. These independent references refine the biological recommendation; they do not imply that the original electronic condition set identified DynAPs in every tissue or that human foci prove a separate soluble pool. This target-level synthesis is not exhaustive coverage of every original cell’s cytoplasm.

Proposed replacements: cytosol dynein axonemal particle

Summary: Refine the conserved germ-cell cytoplasmic location to independently supported cytosol.

Reason: The PMID:10775177 abstract explicitly reports mouse pachytene/diplotene spermatocyte cytoplasmic staining. The same mouse donor O88978 has independent MGI IDA cytosol annotations from PMID:27353389 in spermatocytes and spermatids, supporting the existing conserved cytosol assignment. Use that finer location with explicit curator deference for the unavailable full donor paper. Do not reinterpret the earlier meiotic experiment as human imaging or as a demonstration of germ-cell DynAPs. This target-level synthesis is not exhaustive coverage of every original cell’s cytoplasm.

Proposed replacements: cytosol

Summary: Retain the curated ortholog-supported cytosol location.

Reason: The mouse donor O88978 carries direct MGI IDA cytosol annotations from PMID:27353389, with spermatocyte and spermatid contexts. Its full original was not recovered here, so the donor assay details remain curator-supported. Human studies independently establish intracellular LRRC6 and DynAP localization, but microscopy of cytoplasmic foci is not presented as soluble fractionation or proof of a separate diffuse pool. Retain the conserved cytosol assignment without mislabeling the mouse evidence as a human assay.

Summary: Retain the curated ortholog-supported cytosol location.

Reason: The mouse donor O88978 carries direct MGI IDA cytosol annotations from PMID:27353389, with spermatocyte and spermatid contexts. Its full original was not recovered here, so the donor assay details remain curator-supported. Human studies independently establish intracellular LRRC6 and DynAP localization, but microscopy of cytoplasmic foci is not presented as soluble fractionation or proof of a separate diffuse pool. Retain the conserved cytosol assignment without mislabeling the mouse evidence as a human assay.

Summary: Specify the positively observed motile-cilium context.

Reason: PMID:23122589 reports human control nasal-cell ciliary LRRC6 staining with a mutant specificity control. PMID:23527195 instead reports no axonemal signal in human airway cultures, and PMID:33403504 supports human sperm flagella. Retain the positive source observation and refine to motile cilium, without asserting universal axonemal localization across preparations.

Proposed replacements: motile cilium

Summary: Refine the cilium mapping to the observed motile-cilium context.

Reason: The UniProt subcellular-location mapping is compatible with positive human respiratory-cilium and sperm-flagellum observations. Motile cilium is more informative than all cilia; the later human airway study with no axonemal signal is retained as a contextual discrepancy.

Proposed replacements: motile cilium

Summary: The male-gonad-development inference remains unresolved.

Reason: The mouse donor carries an IEP annotation from PMID:10775177. Its accessible complete abstract establishes meiotic-stage expression and cytoplasmic localization, not by itself developmental progression of the male gonad. Full text was not recovered, and neither male infertility nor defective sperm motility settles that developmental claim. Preserve the original inference without declaring the curator wrong from abstract-only access.

Summary: The male-gonad-development inference remains unresolved.

Reason: The mouse donor carries an IEP annotation from PMID:10775177. Its accessible complete abstract establishes meiotic-stage expression and cytoplasmic localization, not by itself developmental progression of the male gonad. Full text was not recovered, and neither male infertility nor defective sperm motility settles that developmental claim. Preserve the original inference without declaring the curator wrong from abstract-only access.

Summary: Retain the sperm-motility role as a physiological consequence of arm assembly.

Reason: Human LRRC6-associated disease includes severe sperm motility defects with loss of dynein-arm components, supported by respiratory-cell and mouse-ortholog evidence. The specific human patient papers establish sperm context without testing the activity of both natural splice products. Sperm motility is retained outside the compact assembly core.

Summary: Retain the sperm-motility role as a physiological consequence of arm assembly.

Reason: Human LRRC6-associated disease includes severe sperm motility defects with loss of dynein-arm components, supported by respiratory-cell and mouse-ortholog evidence. The specific human patient papers establish sperm context without testing the activity of both natural splice products. Sperm motility is retained outside the compact assembly core.

Summary: Retain the sperm-motility role as a physiological consequence of arm assembly.

Reason: Human LRRC6-associated disease includes severe sperm motility defects with loss of dynein-arm components, supported by respiratory-cell and mouse-ortholog evidence. The specific human patient papers establish sperm context without testing the activity of both natural splice products. Sperm motility is retained outside the compact assembly core.

Summary: Retain contextual motile-cilium localization.

Reason: Human nasal cells and sperm provide positive source-specific ciliary/flagellar observations; a separate airway-culture study finds cytoplasmic LRRC6 and no axonemal signal. This conflict does not justify removing the positive location. The shared assembly function is represented in cytoplasmic DynAPs rather than treating LRRC6 as an axonemal motor component.

Summary: Accept phylogenetically inherited outer-dynein-arm assembly.

Reason: The literal IBD at PTN007663798 is on the human lineage at the opisthokont ancestor and cites mouse MGI:1859553 and human Q86X45. Direct human arm defects and ortholog functional data support the placement. The target appearing among descendant evidence is legitimate experimental grounding, and no lineage-specific loss is indicated.

Summary: Accept the matched outer-arm-assembly rule.

Reason: ARBA00090010 matches the official FunFam 3.80.10.10:FF:000052 and Mammalia conditions. Human dynein-arm pathology independently supports this biological process. The rule match is treated as electronic evidence, not an additional experiment.

Summary: Accept direct human outer-dynein-arm assembly evidence.

Reason: Human mutant respiratory cilia and sperm lack or have reduced outer dynein arms; control staining and ultrastructure locate the defect. The contribution is assembly/axonemal incorporation, not ATP-powered motility or a demonstrated catalytic folding reaction.

Summary: Accept the ortholog-supported outer-arm assembly contribution.

Reason: Mouse Lrrc6 loss leaves ODA proteins in the cytoplasm and removes axonemal outer arms despite preserved IC1–IC2 association. This places its requirement after at least one early subunit association step; it does not negate the broader assembly contribution, which is also directly established in human cells.

Summary: Accept direct human inner-dynein-arm assembly evidence.

Reason: Human patient ultrastructure and inner-arm component staining demonstrate the inner-arm defect alongside outer-arm loss. Retain the distinct inner-arm process within the same integrated cytoplasmic assembly function.

Summary: Accept participation in assembling functional motile cilia through dynein-arm formation.

Reason: The human source identifies absent outer and inner dynein arms, which are components of motile cilia. GO:0044458 covers assembly of components into a motile cilium; persistence of the ciliary projection after LRRC6 loss does not refute participation in that process. The current ontology does not make this term an is_a/part_of ancestor of the two arm-assembly terms, so replacing it would discard valid coverage. PMID:37328841 additionally links LRRC6 to FOXJ1 nuclear accumulation in mouse organoids and transfected HeLa cells, while leaving the direct LRRC6–FOXJ1 connection unresolved. Retain the original assembly assertion together with the more specific arm contributions, without inferring autonomous nuclear-import activity.

Summary: Specify delivery of dynein components to motile cilia.

Reason: The O88978 donor study reports retention of ODA components in the cytoplasm when their ciliary targeting fails; human patient/knockdown findings independently show dynein mislocalization. GO:0120229 captures the established contribution to protein localization within motile cilia. This is a lateral, evidence-directed replacement rather than an is_a/part_of descendant of GO:0051649. It does not identify LRRC6 as a transport motor or prove direct cargo-adaptor activity.

Proposed replacements: protein localization to motile cilium

Summary: Retain the laterality-related ciliary-flow role.

Reason: Human LRRC6-associated primary ciliary dyskinesia includes laterality defects, and mouse Lrrc6 loss disrupts motile-cilia function and laterality. The process is a physiological consequence of the assembly defect; it does not place LRRC6 in extracellular fluid. The matched ARBA or ortholog inference is retained with its original evidence identity.

Summary: Retain the laterality-related ciliary-flow role.

Reason: Human LRRC6-associated primary ciliary dyskinesia includes laterality defects, and mouse Lrrc6 loss disrupts motile-cilia function and laterality. The process is a physiological consequence of the assembly defect; it does not place LRRC6 in extracellular fluid. The matched ARBA or ortholog inference is retained with its original evidence identity.

Summary: Retain the laterality-related ciliary-flow role.

Reason: Human LRRC6-associated primary ciliary dyskinesia includes laterality defects, and mouse Lrrc6 loss disrupts motile-cilia function and laterality. The process is a physiological consequence of the assembly defect; it does not place LRRC6 in extracellular fluid. The matched ARBA or ortholog inference is retained with its original evidence identity.

Summary: Reproductive-system development is not resolved by the available functional evidence.

Reason: The human study establishes infertility, impaired sperm motility and dynein-arm defects. Those findings strongly support reproductive function but do not alone establish the GO developmental process. The ARBA family/taxon condition is real; the source-specific developmental interpretation remains uncertain. Neither source assertion is removed or equated automatically with sperm motility.

Summary: Reproductive-system development is not resolved by the available functional evidence.

Reason: The human study establishes infertility, impaired sperm motility and dynein-arm defects. Those findings strongly support reproductive function but do not alone establish the GO developmental process. The ARBA family/taxon condition is real; the source-specific developmental interpretation remains uncertain. Neither source assertion is removed or equated automatically with sperm motility.

Summary: Specify protein localization to motile cilia.

Reason: The mouse donor and human airway evidence concern delivery/incorporation of dynein components into motile cilia. The narrower imported GO:0120229 captures this context more precisely than localization to any cilium. Assembly defects can cause the localization phenotype; no autonomous transport activity is inferred.

Proposed replacements: protein localization to motile cilium

Summary: Specify protein localization to motile cilia.

Reason: The mouse donor and human airway evidence concern delivery/incorporation of dynein components into motile cilia. The narrower imported GO:0120229 captures this context more precisely than localization to any cilium. Assembly defects can cause the localization phenotype; no autonomous transport activity is inferred.

Proposed replacements: protein localization to motile cilium

Summary: Specify the two dynein-arm assembly contributions.

Reason: The human source documents loss of outer and inner arms and mislocalization or loss of their components after LRRC6 depletion. The outer- and inner-arm processes already present in the source inventory provide precise coverage of the parent assembly term without a new assertion.

Proposed replacements: outer dynein arm assembly inner dynein arm assembly

Summary: Retain the apical cytoplasmic distribution.

Reason: The mouse ortholog assignment is compatible with human LRRC6 concentrated near basal bodies beneath the cilia and with cytoplasmic dynein-assembly foci. This is a supported contextual region of the assembly-factor distribution, not proof that LRRC6 is a basal-body structural component.

Summary: Retain the ortholog-supported cerebrospinal-fluid circulation role.

Reason: Mouse Lrrc6 loss produces hydrocephalus and immotile motile cilia. The later mouse study also examines ependymal ciliary beating. These observations are coherent with the curator-supported CSF-circulation annotation, which is retained as a physiological consequence rather than a separate biochemical function. No direct human CSF-flow experiment is claimed.

Summary: Accept the dynein-component targeting contribution.

Reason: The human airway study shows DNAI1 accumulating below cilia and loss of axonemal dynein components when LRRC6 is deficient. This supports protein localization to motile cilium as part of establishing the functional dynein arms, without isolating the transport mechanism from assembly.

Summary: Accept localization to dynein axonemal particles.

Reason: The literal Xenopus donor A0A1L8G016 has direct tagged-Lrrc6 DynAP evidence in PMID:30561330 and PMID:33263282. Crucially, PMID:30561330 also shows endogenous human airway LRRC6 in dynein-containing cytoplasmic foci. GO:0120293 is an intracellular membraneless organelle, not a stoichiometric protein complex; this annotation does not establish that LRRC6 itself forms the condensate.

Summary: Accept localization to dynein axonemal particles.

Reason: The literal Xenopus donor A0A1L8G016 has direct tagged-Lrrc6 DynAP evidence in PMID:30561330 and PMID:33263282. Crucially, PMID:30561330 also shows endogenous human airway LRRC6 in dynein-containing cytoplasmic foci. GO:0120293 is an intracellular membraneless organelle, not a stoichiometric protein complex; this annotation does not establish that LRRC6 itself forms the condensate.