Clarin-1 is a 232-amino-acid, four-transmembrane (tetraspanin-like) glycoprotein of the clarin family (paralogs CLRN2 and CLRN3), carrying a single N-linked glycosylation site at Asn48 in its first extracellular loop. It is expressed in the sensory hair cells of the inner ear and in the retina. At the plasma membrane it acts as a membrane-associated organizer of the cortical F-actin cytoskeleton rather than as an enzyme, channel, or transporter. In cochlear and vestibular hair cells clarin-1 supports the organization and maintenance of the F-actin-rich stereociliary hair bundle and thereby efficient mechanotransduction, and at the basolateral inner-hair-cell ribbon synapse it organizes cortical actin and the presynaptic calcium-channel machinery required for synaptic maturation and transmission. Clarin-1 traffics through the endoplasmic reticulum and Golgi to the cell surface, and disease-associated variants that disrupt glycosylation or folding (e.g. N48K) are retained and degraded, reducing surface delivery. In the retina, clarin-1 is expressed predominantly in Muller glia and appears to support photoreceptor maintenance non-cell-autonomously. Loss of function causes Usher syndrome type 3A (progressive post-lingual sensorineural hearing loss, variable vestibular dysfunction, and rod-cone retinal degeneration) and non-syndromic retinitis pigmentosa.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0007605 sensory perception of sound | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation of clarin-1 to hearing. This is the best-supported core function of CLRN1: loss of function causes Usher syndrome type 3A with progressive sensorineural hearing loss, and the clarin family has a conserved role in vertebrate hair-cell function. Reason: Core function, concordant with the human IMP evidence (PMID:15650299) and with the role of clarin-1 in organizing the F-actin stereociliary hair bundle required for mechanotransduction. The IBA node placement across the clarin family is sound. |
| GO:0050957 equilibrioception | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to vestibular function. Clarin-1 is expressed in vestibular as well as cochlear hair cells, and USH3A patients show variable vestibular dysfunction, so a role in equilibrioception is a genuine hair-cell function. Reason: Supported by the same hair-bundle F-actin organizing role that underlies hearing, and concordant with the human IMP annotation (PMID:15521980). Vestibular involvement in USH3A is variable but real. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation from the UniProt Subcellular Location mapping (SL-0039). Clarin-1 is a multi-pass cell-membrane protein; this is well corroborated by experimental evidence. Reason: Concordant with EXP (PMID:21310491) and IDA (PMID:19423712) plasma-membrane annotations and with UniProt's curated Cell membrane subcellular location. Core compartment where clarin-1 functions. |
| GO:0007605 sensory perception of sound | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning electronic annotation to hearing, duplicating the IBA and IMP annotations for the same term. Reason: Correct core function; duplicate of well-supported experimental (PMID:15650299) and phylogenetic evidence. Duplicate GO terms across evidence codes are acceptable. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: All 27 GOA "protein binding" IPI rows for CLRN1 derive from a single systematic yeast-two-hybrid screen, the human binary reference interactome (HuRI/HI-III-20; PMID:32296183). The recovered partners (e.g. ALG8, MGST3, SEC22B, ITGAM, CLDN19, multiple TMEM proteins) are largely ER/membrane proteins and do not include the physiologically meaningful interactors (harmonin/USH1C, CACNB2). Bare "protein binding" conveys no specific molecular function. Reason: GO:0005515 is uninformative as a molecular-function annotation, and these come from a high-throughput binary screen with no functional follow-up for clarin-1. Per curation guidelines, bare protein binding should not be endorsed as a core function. Retained (not removed) because the interactions are experimentally recorded, but flagged as over-annotation. Supporting Evidence: PMID:32296183 yeast two-hybrid (Y2H) represents the only binary PPI assay that can be operated at sufficient throughput to systematically screen the human proteome for binary PPIs |
| GO:0015630 microtubule cytoskeleton | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from the mouse ortholog (Q8K445) by Ensembl Compara. Clarin-1 is consistently linked to the F-actin cytoskeleton, not the microtubule cytoskeleton; there is no experimental support for a microtubule localization. Reason: Biologically unsupported and likely an over-propagated electronic transfer. All direct evidence places clarin-1's cytoskeletal role with F-actin (PMID:19423712), making a microtubule-cytoskeleton localization implausible as a functional annotation. |
| GO:0030140 trans-Golgi network transport vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation transferred from the mouse ortholog. Clarin-1 is N-glycosylated and matures through the ER and Golgi en route to the plasma membrane, so it transiently occupies the Golgi/trans-Golgi trafficking pathway. Reason: Reflects a trafficking-transit compartment rather than the site where clarin-1 carries out its function (plasma membrane / stereocilia). Consistent with the Endo H-resistant, Golgi-processed glycan reported for clarin-1, but non-core. Supporting Evidence: PMID:19423712 Resistance to Endo H f suggests that the N -linked glycan moiety on CLRN1 was processed by Golgi-mannosidase II and passed through the protein quality control mechanism of the Golgi apparatus |
| GO:0032420 stereocilium | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic annotation transferred from the mouse ortholog. The stereocilium is a core site of clarin-1 action: it localizes to the F-actin-rich stereociliary hair bundle, and Clrn1-null hair cells show disorganized stereocilia. Reason: Well supported by mouse in-vivo evidence that clarin-1 is required for stereocilia organization (PMID:19423712). This is a central, correct localization for the wild-type hair-bundle function. Supporting Evidence: PMID:19423712 F-actin-enriched stereocilia of auditory hair cells evidenced structural disorganization in Clrn1 |
| GO:0045178 basal part of cell | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic annotation transferred from the mouse ortholog. In addition to its apical stereociliary pool, clarin-1 has a basolateral pool at the inner-hair-cell ribbon synapse, consistent with a basal-part-of-cell localization. Reason: Concordant with the reported basolateral ribbon-synapse localization of clarin-1 in inner hair cells (deep research: Dulon et al. 2018, JCI94351). A correct location for one of clarin-1's functional pools. |
| GO:0005886 plasma membrane | EXP PMID:21310491 CLRN1 mutations cause nonsyndromic retinitis pigmentosa. | ACCEPT | Summary: Experimental (EXP) plasma-membrane localization from the study of CLRN1 RP61 variants, which showed wild-type clarin-1 at the cell membrane while RP-causing mutants were retained in the ER (abstract-only in cache; full text read by the original curator). Reason: Correct core compartment, corroborated by UniProt's curated Cell membrane location (ECO:0000269|PubMed:21310491) and by independent IDA evidence (PMID:19423712). |
| GO:0005886 plasma membrane | IDA PMID:19423712 Clarin-1, encoded by the Usher Syndrome III causative gene, ... | ACCEPT | Summary: Direct assay (IDA): clarin-1 expressed in HEK293 cells localized to the plasma membrane, demonstrated by co-localization with Na/K-ATPase and by cell-surface biotinylation. Reason: Correct core compartment. Although demonstrated in a heterologous cell line, the plasma-membrane localization is independently confirmed by EXP evidence (PMID:21310491) and by the biology of a multi-pass membrane protein. Supporting Evidence: PMID:19423712 We found that CLRN1 localized to the plasma membrane when expressed in HEK293 cells. |
| GO:0005902 microvillus | IDA PMID:19423712 Clarin-1, encoded by the Usher Syndrome III causative gene, ... | MARK AS OVER ANNOTATED | Summary: Direct assay: in HEK293 cells, overexpressed clarin-1 was enriched in microvilli and lamellipodia, co-localizing with F-actin and Na/K-ATPase. Reason: This is a heterologous-overexpression readout in a non-sensory immortalized cell line. The physiologically relevant actin-based projection for clarin-1 is the hair-cell stereocilium (a specialized microvillus-like structure), which is separately and better annotated. The generic microvillus localization reflects the HEK293 model rather than the wild-type in-vivo site of action. Supporting Evidence: PMID:19423712 On the plasma membrane, CLRN1 was especially enriched in microvilli and lamellipodia |
| GO:0007015 actin filament organization | IDA PMID:19423712 Clarin-1, encoded by the Usher Syndrome III causative gene, ... | ACCEPT | Summary: Direct assay: clarin-1 reorganizes actin filament structures. Wild-type clarin-1 concentrated F-actin at cellular protrusions in HEK293 cells, and this activity was lost in the N48K USH3A mutant; in vivo, Clrn1-null hair cells showed disorganized F-actin stereocilia. Reason: This captures clarin-1's core molecular role as an organizer of the F-actin cytoskeleton, which underlies its function in stereociliary hair-bundle integrity. The in-cell activity is corroborated by the in-vivo stereocilia phenotype in Clrn1-null mice and by loss of the activity in the disease mutant. Supporting Evidence: PMID:19423712 Clarin-1 reorganized actin filament structures and induced lamellipodia. PMID:19423712 These observations suggest a possible role for clarin-1 in the regulation and homeostasis of actin filaments, and link clarin-1 to the interactive network of Usher syndrome gene products. |
| GO:0010592 positive regulation of lamellipodium assembly | IDA PMID:19423712 Clarin-1, encoded by the Usher Syndrome III causative gene, ... | MARK AS OVER ANNOTATED | Summary: Direct assay: overexpression of clarin-1 in HEK293 cells induced lamellipodia and cellular spreading. Reason: Lamellipodium induction is a downstream consequence of clarin-1's actin-organizing activity observed under heterologous overexpression in HEK293 cells, not a physiological function of clarin-1 in sensory hair cells (which do not form lamellipodia). It is better captured by the actin filament organization annotation; retained but flagged as an over-annotation of the model-system phenotype. Supporting Evidence: PMID:19423712 These results suggest that wild-type CLRN1 locally activates cellular spreading and an increase in the number of cellular protrusions. |
| GO:0030027 lamellipodium | IDA PMID:19423712 Clarin-1, encoded by the Usher Syndrome III causative gene, ... | MARK AS OVER ANNOTATED | Summary: Direct assay: clarin-1 localized to lamellipodial protrusions in HEK293 cells, where F-actin was concentrated. Reason: The lamellipodium is an actin structure formed by the HEK293 heterologous-expression system and not a compartment relevant to clarin-1's wild-type role in hair cells. Reflects the model system rather than in-vivo localization; retained but flagged. Supporting Evidence: PMID:19423712 On the plasma membrane, CLRN1 was especially enriched in microvilli and lamellipodia |
| GO:0048870 cell motility | IDA PMID:19423712 Clarin-1, encoded by the Usher Syndrome III causative gene, ... | MARK AS OVER ANNOTATED | Summary: Direct assay: clarin-1 overexpression increased motility/spreading of HEK293 cells, with recruitment of integrin and N-cadherin to protrusions. Reason: Cell motility is a phenotype of clarin-1 overexpression in a migratory immortalized cell line and is not a wild-type function of clarin-1 in post-mitotic, non-motile sensory hair cells. It is a manifestation of the underlying actin-organizing activity rather than a distinct physiological role; retained but flagged as an over-annotation. Supporting Evidence: PMID:19423712 These results suggest that wild-type CLRN1 locally activates cellular spreading and an increase in the number of cellular protrusions. |
| GO:0045494 photoreceptor cell maintenance | IMP PMID:15521980 Mutation screening of USH3 gene (clarin-1) in Spanish patien... | KEEP AS NON CORE | Summary: IMP from a human USH3A patient mutation-screening study (abstract-only in cache): CLRN1 loss-of-function is associated with rod-cone retinal degeneration, so clarin-1 is required for photoreceptor maintenance at the organismal level. Reason: The retinal phenotype is genuine, but recent evidence localizes clarin-1 predominantly to Muller glia rather than photoreceptors, implying a non-cell-autonomous, supportive role in photoreceptor maintenance. The core function of clarin-1 is in hair-cell F-actin/hair-bundle organization; retinal maintenance is kept as a non-core involvement. Human IMP from patient studies is acceptable, and the full text was read by the original curator. |
| GO:0007605 sensory perception of sound | IMP PMID:15650299 Serial audiometry and speech recognition findings in Finnish... | ACCEPT | Summary: IMP from serial audiometry of Finnish USH3 patients (abstract-only in cache), documenting the progressive hearing loss caused by CLRN1 loss of function. Reason: Directly supports the core role of clarin-1 in hearing from human patient data. Concordant with the IBA and ARBA annotations to the same term. |
| GO:0050953 sensory perception of light stimulus | IMP PMID:15521980 Mutation screening of USH3 gene (clarin-1) in Spanish patien... | KEEP AS NON CORE | Summary: IMP from a human USH3A patient study (abstract-only in cache): CLRN1 mutations cause retinitis pigmentosa, impairing vision, hence involvement in the sensory perception of light. Reason: A genuine consequence of CLRN1 loss (rod-cone degeneration), but the retinal role is non-cell-autonomous (via Muller glia) and secondary to the core hair-cell function. Kept as a non-core involvement rather than a defining function. |
| GO:0050957 equilibrioception | IMP PMID:15521980 Mutation screening of USH3 gene (clarin-1) in Spanish patien... | ACCEPT | Summary: IMP from a human USH3A patient study (abstract-only in cache): USH3A patients show variable vestibular dysfunction, consistent with a role for clarin-1 in vestibular hair-cell function and equilibrioception. Reason: A genuine hair-cell function, supported by human patient phenotype data and concordant with the IBA annotation. Rests on the same stereociliary F-actin organizing role as hearing. |
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