id: B0UYJ1 gene_symbol: lhfpl5b product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:7955 label: Danio rerio description: lhfpl5b (LHFPL tetraspan subfamily member 5b) is one of two zebrafish co-orthologs of vertebrate LHFPL5 (TMHS), retained from the teleost-specific genome duplication; its paralog is lhfpl5a. It encodes a small four-pass membrane protein of the tetraspan junctional protein superfamily, an accessory subunit of the hair-cell mechanoelectrical transduction (MET) complex. lhfpl5b is expressed only in hair cells of the lateral-line neuromasts, from about 2 dpf, and not in the inner ear. lhfpl5b loss-of-function mutants (vo35, a frameshift that removes three of the four transmembrane helices) lose transduction in almost all lateral-line hair cells and have fewer neuromast hair cells, while hearing and balance are normal; the mutants are adult viable. Expression of Lhfpl5a in lhfpl5b mutant hair cells restores lateral-line transduction. Tmc2b still reaches the hair bundle without Lhfpl5b. Because they lack only lateral-line function, lhfpl5b mutants have been used to show lateral-line roles in swim-bladder inflation and in social regulation of pth2 expression. existing_annotations: - term: id: GO:0003674 label: molecular_function evidence_type: ND original_reference_id: GO_REF:0000015 qualifier: enables review: summary: Root-term ND placeholder recording that no molecular function had been curated for lhfpl5b. action: ACCEPT reason: >- ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the molecular function is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: REMOVE. The zebrafish data (PMID:32009898) show lhfpl5b is required for lateral-line transduction, which is necessity, not a molecular activity; the accessory-subunit activity rests on mouse LHFPL5. Possibly stale: the 2026-11-06 ND citation pass found literature on this gene in this species that may identify a molecular function; see lhfpl5b-notes.md, section "ND literature-search citations (2026-11-06)". A curator should check it before this ACCEPT stands. - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - MGI:MGI:1915382 - MGI:MGI:3057108 - PANTHER:PTN000968268 - RGD:727967 review: summary: Plasma membrane location propagated across the LHFPL family. action: ACCEPT reason: Four-pass membrane protein of the hair-bundle MET complex; the paralog's tagged protein sits at stereocilia tips. No Lhfpl5b localization data exist, but the protein conserves the family structure. supported_by: - reference_id: PMID:32009898 supporting_text: Alignment of the zebrafish Lhfpl5a and Lhfpl5b proteins with those from human, mouse and chicken reveals that both zebrafish ohnologs retain the same protein structure (Figure 1B). - term: id: GO:0007605 label: sensory perception of sound evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - FB:FBgn0262624 - MGI:MGI:1915382 - PANTHER:PTN000968268 review: summary: Sensory perception of sound, from the PANTHER LHFPL5 node. action: MARK_AS_OVER_ANNOTATED reason: 'The IBA node is sound for the family and the Lhfpl5b protein can probably do the job, but this copy is not expressed in the ear: larval in situ hybridization finds it only in neuromasts, lhfpl5b mutants have normal inner-ear microphonics and hearing, and adult inner-ear hair cells express lhfpl5a but not lhfpl5b. The lateral line detects water motion, not sound. The division of labour arose by expression partition after the duplication, which a same-node IBA cannot see. Whether adult lhfpl5b contributes to hearing has not been tested directly, so the row is marked rather than removed.' supported_by: - &id003 reference_id: PMID:32009898 supporting_text: 'Here we show that the zebrafish lhfpl5 genes are expressed in discrete populations of hair cells: lhfpl5a expression is restricted to auditory and vestibular hair cells in the inner ear, while lhfpl5b expression is specific to hair cells of the lateral line organ.' - reference_id: PMID:32009898 supporting_text: Thus, lhfpl5atm290d mutants exhibit defects in inner ear function, while the lhfpl5bvo35 mutation has no effect on these hair cells. - reference_id: PMID:39484049 supporting_text: Zebrafish HCs expressed ush1c, tmie, pcdh15a/b, and lhfpl5a, but not the paralog lhfpl5b, while mouse HCs expressed the orthologs Ush1c, Tmie, Pcdh15, and Lhfpl5, respectively. - reference_id: PMID:32009898 supporting_text: Future studies on adults will determine whether the lateral line remains non-functional and whether lhfpl5b contributes to inner ear function in the mature auditory and vestibular systems. propagation_review: root_cause: PROPAGATION_BAD failure_modes: - CONTEXT_OR_TISSUE_MISMATCH source_entities: - source_id: PANTHER:PTN000968268 source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET comment: The LHFPL5 node rightly carries sound perception for mouse Lhfpl5 and for lhfpl5a, but lhfpl5b lost inner-ear expression after the teleost duplication and its mutants hear normally. - source_id: MGI:MGI:1915382 source_label: Lhfpl5 (mouse) source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET comment: Mouse Lhfpl5 is required for cochlear transduction; the function transfers to the protein but not to this copy's biological role. - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0162 review: summary: Membrane, from UniProt subcellular location. action: ACCEPT reason: Correct; the protein has the four transmembrane helices of the family (UniProt predicts three, but the published alignment shows the same four-helix structure as Lhfpl5a). supported_by: - reference_id: PMID:32009898 supporting_text: This mutation disrupts the protein in the first extracellular loop and deletes the final three of four transmembrane helices in Lhfpl5b. - term: id: GO:0035678 label: neuromast hair cell morphogenesis evidence_type: IMP original_reference_id: PMID:32009898 qualifier: acts_upstream_of_or_within supporting_entities: - ZFIN:ZDB-GENO-200824-4 review: summary: Neuromast hair cell morphogenesis, from the reduced number of neuromast hair cells in lhfpl5b vo35 mutants. action: MARK_AS_OVER_ANNOTATED reason: The paper reports fewer hair cells per neuromast, not a change in hair-cell shape, and interprets the reduction as a consequence of lost transduction, as seen in other transduction mutants (myo7aa, pcdh15a, tomt). Lhfpl5b is a MET complex subunit and there is no evidence that it acts in hair-cell morphogenesis. supported_by: - reference_id: PMID:32009898 supporting_text: This decrease in the number of neuromast hair cells is consistent with lhfpl5b mutants being deficient in mechanotransduction in this cell type. - reference_id: PMID:32009898 supporting_text: We have previously reported a reduced number of neuromast hair cells in other transduction mutants such as myo7aa (mariner), pcdh15a (orbiter), and tomt (mercury) (Seiler et al., 2005; Erickson et al., 2017). - term: id: GO:0050974 label: detection of mechanical stimulus involved in sensory perception evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:1915382 - PANTHER:PTN002647973 - ZFIN:ZDB-GENE-110131-8 review: summary: Detection of mechanical stimulus involved in sensory perception, from the PANTHER LHFPL5 node. action: ACCEPT reason: 'Core process for this copy: lhfpl5b mutants lose transduction in lateral-line hair cells and the lateral line is silenced. The lhfpl5a donor in WITH/FROM is appropriate because the two proteins are interchangeable in the rescue assay.' supported_by: - reference_id: PMID:32009898 supporting_text: CRISPR-Cas 9 knockout of lhfpl5b alone silences the lateral line organ but has no effect on otic hair cell function. - &id001 reference_id: PMID:32009898 supporting_text: Strikingly, lateral line hair cells in lhfpl5bvo35 mutants do not label with FM 1–43 while there is no difference in the intensity of FM 1–43 labeling of hair cells between WT and lhfpl5atm290d mutants - &id002 reference_id: PMID:32009898 supporting_text: The loss of MET channel activity in lhfpl5bvo35 neuromasts is rescued by expression of the GFP-lhfpl5a vo23Tg transgene (Figures 4I,J; n = 7/7 mutant individuals). This result indicates that Lhfpl5a and Lhfpl5b are functionally interchangeable in this context. references: - id: GO_REF:0000015 title: Use of the ND evidence code for Gene Ontology (GO) terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: PMID:32009898 title: The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text. lhfpl5b vo35 (CRISPR, S77FfsX48) silences the lateral line; expression restricted to neuromast hair cells; rescued by GFP-Lhfpl5a. - id: PMID:39484049 title: Molecular specializations underlying phenotypic differences in inner ear hair cells of zebrafish and mice. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text. Adult zebrafish inner-ear hair cells express lhfpl5a but not lhfpl5b. - id: PMID:38194445 title: LHFPL5 is a key element in force transmission from the tip link to the hair cell mechanotransducer channel. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text. Mouse; LHFPL5 is a principal component of the gating spring. - id: PMID:37272538 title: 'A sensation for inflation: initial swim bladder inflation in larval zebrafish is mediated by the mechanosensory lateral line.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text. Uses lhfpl5b vo35 as a lateral-line-only mutant; transgenic Lhfpl5a rescue restores normal swim-bladder inflation. - id: PMID:36161311 title: 'Alone in a crowd: effect of a nonfunctional lateral line on expression of the social hormone parathyroid hormone 2.' findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Full text. Uses lhfpl5b vo35 as a lateral-line-only mutant (pth2 expression). - id: PMID:36598134 title: Single-cell transcriptomic profiling of the zebrafish inner ear reveals molecularly distinct hair cell and supporting cell subtypes. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Full text. lhfpl5b used as a lateral-line hair-cell marker. - id: file:DANRE/lhfpl5a/lhfpl5a-bioinformatics/RESULTS.md title: lhfpl5a / lhfpl5b identity, conserved synteny and expression records reference_review: relevance: HIGH correctness: VERIFIED review_notes: Manual audit verified the sidecar supports a teleost-duplication origin and the reported ear/lateral-line expression split; it notes that the public curated expression mirrors the publications rather than providing an independent functional test. findings: [] core_functions: - description: Accessory transmembrane subunit of the MET complex in lateral-line hair cells, required for their mechanotransduction; functionally interchangeable with Lhfpl5a, which it replaces in the lateral line because of expression, not protein, differences. Recorded as a contribution to the channel complex's activity. contributes_to_molecular_function: id: GO:0140135 label: mechanosensitive monoatomic cation channel activity directly_involved_in: - id: GO:0050974 label: detection of mechanical stimulus involved in sensory perception locations: - id: GO:0005886 label: plasma membrane supported_by: - *id003 - *id001 - *id002 - &id004 reference_id: PMID:38194445 supporting_text: We conclude that tip-link tension is transmitted to the channel primarily via LHFPL5; residual activation without LHFPL5 may occur by direct interaction between PCDH15 and TMC1. suggested_questions: - question: Does GFP-Lhfpl5b localize to stereocilia tips of neuromast hair cells and depend on Pcdh15a, as Lhfpl5a does in the ear? - question: Does lhfpl5b contribute to inner-ear function in adults, or does the adult lateral line remain silent in lhfpl5b mutants? - question: Which protein supports the residual FM labeling in a few neuromast hair cells (most reproducibly SO3) of lhfpl5a/lhfpl5b double mutants — another LHFPL family member? suggested_experiments: - hypothesis: Lhfpl5b can replace Lhfpl5a in the inner ear. description: Express GFP-Lhfpl5b from the myo6b or lhfpl5a promoter in lhfpl5a tm290d mutants and test acoustic startle, inner-ear microphonics and FM dye uptake (the reciprocal of the published Lhfpl5a rescue of lhfpl5b mutants). experiment_type: cross-rescue - hypothesis: The lateral-line restriction of lhfpl5b is set by its proximal promoter. description: Map the elements in the 2 kb lhfpl5b upstream region (used by Venuto et al. 2023 to drive ChR2 in lateral-line hair cells) and compare with gar lhfpl5 upstream sequence in reporter assays. experiment_type: enhancer reporter assay