Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Electronic Gene Ontology annotations created by ARBA machine learning models
Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans.
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In the samba mouse model, a Loxhd1 mutation leaves stereociliary development intact but perturbs hair-cell function and is followed by hair-cell degeneration.
"Stereociliary development is unaffected in samba mice, but hair cell function is perturbed and hair cells eventually degenerate."
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Mouse LOXHD1 is a PLAT-repeat protein localized along the membrane of mature hair-cell stereocilia.
"LOXHD1 consists entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains and is expressed along the membrane of mature hair cell stereocilia."
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A human LOXHD1 mutation was identified as the cause of DFNB77, a progressive autosomal-recessive nonsyndromic hearing-loss phenotype.
"Based on the studies in mice, we screened DNA from human families segregating deafness and identified a mutation in LOXHD1, which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL)."
Loxhd1 Mutations Cause Mechanotransduction Defects in Cochlear Hair Cells.
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Two mouse alleles affecting PLAT repeat 10 caused a late-onset inner-hair-cell mechanotransduction defect: currents were near wild type at P7 but drastically reduced at P11.
"Using two mouse mutants of LOXHD1-PLAT10, we demonstrated here that inner hair cell (IHC) mechanotransduction currents were drastically reduced at P11, in contrast to the wild-type (WT)-like MET currents observed at P7."
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The mouse mechanotransduction defect preceded gross bundle disruption and occurred while key upper- and lower-tip-link complex proteins remained localized.
"The Loxhd1 MET defect was novel, as it occurred without an altered hair bundle structure or mislocalization of key upper (Harmonin) or lower (LHFPL5) TL complex proteins."
LOXHD1 is indispensable for maintaining TMC1 auditory mechanosensitive channels at the site of force transmission.
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In mouse inner hair cells, LOXHD1 is required to maintain TMC1 in stereocilia and near the shorter-stereocilium tip where the lower tip link inserts.
"Overall, these SUB-immunogold-SEM experiments support that LOXHD1 is required for the maintenance of TMC1 in IHC stereocilia. Importantly, LOXHD1 is also critical for maintenance of TMC1 within the first 100 nm of the row 2 tips, where the tip links insert and where the mechanical stimuli are received."
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Full-length tagged LOXHD1 selectively co-immunoprecipitated with TMC1 but not TMC2 in heterologous HEK293T-cell assays.
"These experiments demonstrate that LOXHD1 interacts selectively in vitro with TMC1 but not with TMC2."
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Mouse in-situ nanoscale localization places LOXHD1 in protein complexes attached to the lower tip-link branches.
"Thus, we conclude that as for TMC1, LOXHD1 proteins are integral to protein complexes attached to the lower tip-link branches in vivo."
Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1.
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Ewing-sarcoma cells express an alternative human LOXHD1 short isoform with 13 PLAT repeats and one coiled-coil region, rather than the full 15-PLAT-repeat architecture.
"The short isoform LOXHD1 contains 33 exons and codes for 1891 aa protein containing 13 PLAT and 1 coiled-coil domains (Figure 2B)."
UniProtKB entry Q8IVV2 (LOXH1_HUMAN), Lipoxygenase homology domain-containing protein 1
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The reviewed human entry lists four alternatively spliced isoforms.
"CC Event=Alternative splicing; Named isoforms=4;"
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Pfam maps 15 PLAT domains in the displayed human sequence.
"DR Pfam; PF01477; PLAT; 15."
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UniProtKB currently assigns human LOXHD1 protein evidence at transcript level.
"PE 2: Evidence at transcript level;"
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The human stereocilium localization is annotated by sequence similarity rather than direct experimental evidence in human cochlear tissue.
"CC -!- SUBCELLULAR LOCATION: Cell projection, stereocilium {ECO:0000250}."
Falcon deep research report for LOXHD1
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Independent literature synthesis concludes that LOXHD1 is best modeled as a nonenzymatic stereociliary protein that couples the mature TMC1-containing mechanotransduction complex to the lower tip-link force-transmission site.
"The strongest current model is that it is a **stereociliary structural/adaptor protein** that couples the mature, TMC1-containing auditory mechanotransduction complex to the lower tip-link force-transmission site."
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No catalytic activity has been established for LOXHD1 despite the lipoxygenase homology in its name, supporting the decision not to assign a molecular-function term.
"No catalytic residues, reaction, substrate specificity, kinetic constants, or small-molecule products have been established."
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The mechanistic evidence base is mouse; the report explicitly notes the absence of equivalent human-cochlear localization data, supporting the ISO framing of the proposed refined annotations.
"equivalent nanoscale localization in human cochlear tissue has not been demonstrated in the retrieved sources"
LOXHD1 bioinformatics analysis of PLAT-repeat architecture and isoform boundaries
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The displayed human LOXHD1 sequence is a near-continuous 15-PLAT-domain array without a separately annotated catalytic domain.
"The curated Q8IVV2 sequence is a near-continuous array of 15 annotated PLAT domains (residues 43-2064), with no separately annotated catalytic domain."
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Coordinate mapping shows that the shorter curated isoforms retain substantially different subsets of the displayed sequence's PLAT repeats.
"Q8IVV2-3 loses repeats 1-6, deletes 92 of 121 annotated residues in repeat 7, retains repeats 8-14, and alters repeat 15 through a 12-residue replacement followed by deletion from residue 2020 onward. - Q8IVV2-4 loses repeats 1-11, deletes the first four annotated residues of repeat 12, retains repeats 13-14, and deletes the C-terminal 52 annotated residues of repeat 15. - Q8IVV2-5 loses repeats 1-11, deletes the first four annotated residues of repeat 12, and retains repeats 13-15."