ESPN

Summary

ESPN (espin, HGNC:13281) is a protein-coding gene on chromosome 1p36.31, encoding Espin (B1AK53). Multifunctional actin-bundling protein.

This gene encodes a multifunctional actin-bundling protein. It plays a major role in regulating the organization, dimensions, dynamics, and signaling capacities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in various mechanosensory and chemosensory cells. Mutations in this gene are associated with autosomal recessive neurosensory deafness, and autosomal dominant sensorineural deafness without vestibular involvement.

Source: NCBI Gene 83715 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 596 total — 14 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 22
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_031475

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13281
Approved symbol	ESPN
Name	espin
Location	1p36.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000187017
Ensembl biotype	protein_coding
OMIM	606351
Entrez	83715

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000418286, ENST00000434576, ENST00000461727, ENST00000468561, ENST00000475228, ENST00000475479, ENST00000477679, ENST00000478323, ENST00000632142, ENST00000632593, ENST00000632803, ENST00000633239, ENST00000633651, ENST00000636330, ENST00000636644, ENST00000645284

RefSeq mRNA: 3 — MANE Select: NM_031475 NM_001367473, NM_001367474, NM_031475

CCDS: CCDS70

Canonical transcript exons

ENST00000645284 — 13 exons

Exon	Start	End
ENSE00001607954	6440254	6440440
ENSE00001628075	6428226	6428419
ENSE00001652588	6444481	6444682
ENSE00001663987	6448641	6449091
ENSE00001694857	6459999	6460944
ENSE00001726498	6440934	6441065
ENSE00001750382	6440626	6440808
ENSE00002140881	6445664	6445935
ENSE00003544352	6451603	6451748
ENSE00003610124	6451833	6452096
ENSE00003630784	6457184	6457263
ENSE00003685596	6457361	6457372
ENSE00003825592	6424776	6425249

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 98.80.

FANTOM5 (CAGE): breadth broad, TPM avg 4.4751 / max 476.3177, expressed in 563 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
381	2.9652	363
385	0.5012	160
387	0.1636	44
393	0.1433	37
396	0.1174	39
384	0.1100	48
386	0.0963	35
392	0.0827	32
390	0.0756	23
398	0.0698	21

Top tissues by expression

236 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	98.80	gold quality
left testis	UBERON:0004533	98.79	gold quality
right uterine tube	UBERON:0001302	97.93	gold quality
right lobe of liver	UBERON:0001114	97.27	gold quality
mucosa of transverse colon	UBERON:0004991	96.81	gold quality
testis	UBERON:0000473	96.23	gold quality
skin of abdomen	UBERON:0001416	94.56	gold quality
skin of leg	UBERON:0001511	93.64	gold quality
liver	UBERON:0002107	93.58	gold quality
kidney epithelium	UBERON:0004819	93.52	gold quality
ileal mucosa	UBERON:0000331	93.51	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.35	gold quality
adult mammalian kidney	UBERON:0000082	93.16	gold quality
metanephros cortex	UBERON:0010533	92.81	gold quality
lower esophagus mucosa	UBERON:0035834	92.75	gold quality
upper arm skin	UBERON:0004263	91.79	silver quality
zone of skin	UBERON:0000014	91.17	gold quality
adenohypophysis	UBERON:0002196	90.38	gold quality
pituitary gland	UBERON:0000007	90.06	gold quality
jejunal mucosa	UBERON:0000399	89.40	gold quality
duodenum	UBERON:0002114	89.32	gold quality
esophagus mucosa	UBERON:0002469	89.01	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.54	gold quality
buccal mucosa cell	CL:0002336	88.36	silver quality
small intestine	UBERON:0002108	88.25	gold quality
transverse colon	UBERON:0001157	87.23	gold quality
kidney	UBERON:0002113	85.38	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.29	gold quality
sural nerve	UBERON:0015488	84.26	gold quality
metanephros	UBERON:0000081	83.89	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	64.56
E-CURD-114	yes	11.36
E-ANND-3	yes	3.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

59 targeting ESPN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4291	99.20	68.88	2969

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 11)

• human deafness and vestibular dysfunction co-segregated with either of two frameshift mutations in ESPN. (PMID:15286153)
• The results further strengthen the causative role of the espin gene in non-syndromic hearing loss and add new insights into espin structure and function. (PMID:15930085)
• Here, we report a new activity of the espins, one that depends on their enigmatic WH2 domain: the ability to assemble a large actin bundle when targeted to a specific subcellular location. (PMID:16569662)
• A recessive ESPN mutation causing congenital hearing loss in a Morocan family was reported. (PMID:18973245)
• Flies with mutations affecting the diaphanous,forked, and CG12026/TMHS genes displayed significant reductions in the amplitude of sound-evoked potentials compared to wild-type flies (PMID:19102128)
• The espin actin-filament-binding site has a major effect on the formation and dynamics of actin bundles. (PMID:24424026)
• The structures of Myo3 in complex with Espin1 not only elucidate the mechanism of the binding, but also reveal a Myo3-induced release of Espin1 auto-inhibition mechanism. (PMID:26785147)
• The utricles were then treated with a gamma-secretase inhibitor, followed by espin or control transduction and histochemistry. Although gamma-secretase inhibition increased the number of HCs, few had stereociliary arrays. In contrast, 46 h after espin1 transduction, a significant increase in hair-bundle-like structures was observed (PMID:26886463)
• A significant inverse correlation was observed between miR-612 and Espin protein expression in melanoma tissues. (PMID:29385671)
• ur study uncovers an additional USH gene, assigns the USH1 phenotype to a variant of ESPN and provides a 12th molecular component to the USH proteome (PMID:29572253)
• whirlin-espin interaction is important for the architecture of the USH2 complex and actin bundles cross-linked by espin. Our demonstration of whirlin N-terminal fragment interaction with espin, is significantly novel, providing insight into how these two proteins interact to form the USH2 complex. (PMID:31638198)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	espn	ENSDARG00000076414
mus_musculus	Espn	ENSMUSG00000028943
rattus_norvegicus	Espn	ENSRNOG00000010270
drosophila_melanogaster	f	FBGN0262111
caenorhabditis_elegans		WBGENE00012319

Paralogs (1): ESPNL (ENSG00000144488)

Protein

Protein identifiers

Espin — B1AK53 (reviewed: B1AK53)

Alternative names: Autosomal recessive deafness type 36 protein, Ectoplasmic specialization protein

All UniProt accessions (12): A0A0J9YW00, A0A0J9YWQ8, A0A0J9YY76, A0A1B0GUN9, A0A1B0GUS9, A0A2R8Y6D3, A0A2R8Y7L7, A0A2R8YG57, B1AK53, H0Y7L4, K7EMB7, Q5JYL1

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional actin-bundling protein. Plays a major role in regulating the organization, dimension, dynamics and signaling capacities of the actin filament-rich microvilli in the mechanosensory and chemosensory cells. Required for the assembly and stabilization of the stereociliary parallel actin bundles. Plays a crucial role in the formation and maintenance of inner ear hair cell stereocilia. Involved in the elongation of actin in stereocilia. In extrastriolar hair cells, required for targeting MYO3B to stereocilia tips, and for regulation of stereocilia diameter and staircase formation.

Subunit / interactions. Monomer. Binds F-actin in a Ca(2+)-resistant fashion. Interacts (via N-terminus) with BAIAP2 (via SH3-domain). Interacts with PFN2. Interacts with MYO3A (via C-terminus). Interacts with MYO3B (via C-terminus).

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Stereocilium. Microvillus.

Disease relevance. Deafness, autosomal recessive, 36, with or without vestibular involvement (DFNB36) [MIM:609006] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNB36 is characterized by prelingual, profound hearing loss, and vestibular areflexia in some patients. The disease is caused by variants affecting the gene represented in this entry. Usher syndrome 1M (USH1M) [MIM:618632] A form of Usher syndrome, a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1M is an autosomal recessive disease characterized by prelingual sensorineural hearing loss, vestibular dysfunction, night blindness, and progressive impairment of vision. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The WH2-domain binds actin monomer and mediates actin bundle assembly.

Isoforms (2)

UniProt ID	Names	Canonical?
B1AK53-1	1	yes
B1AK53-2	2

RefSeq proteins (3): NP_001354402, NP_001354403, NP_113663* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR003124	WH2_dom	Domain
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR052420	Espin/Espin-like	Family

Pfam: PF02205, PF12796, PF13637

UniProt features (49 total): compositionally biased region 10, repeat 9, sequence variant 8, modified residue 6, region of interest 5, sequence conflict 4, splice variant 2, mutagenesis site 2, chain 1, domain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-B1AK53-F1	68.76	0.38

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 338, 342, 515, 647, 690, 696

Mutagenesis-validated functional residues (2):

Position	Phenotype
790–795	no effect on localization to microvilli. no effect on microvillar elongation.
790–795	loss of targeting to microvilli. impaired microvillar elongation.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 211 (showing top): GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, BENPORATH_ES_WITH_H3K27ME3, MODULE_255, RORA1_01, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, MODULE_317, WHITE_NEUROBLASTOMA_WITH_1P36.3_DELETION, GOBP_ACTIN_FILAMENT_ORGANIZATION, GOBP_SENSORY_PERCEPTION, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, GOMF_ACTIN_BINDING, GOCC_NEURON_PROJECTION, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_MICROVILLUS_ORGANIZATION, WONG_ENDMETRIUM_CANCER_UP

GO Biological Process (3): sensory perception of sound (GO:0007605), microvillar actin bundle assembly (GO:0030034), actin filament bundle assembly (GO:0051017)

GO Molecular Function (4): SH3 domain binding (GO:0017124), actin filament binding (GO:0051015), actin binding (GO:0003779), protein binding (GO:0005515)

GO Cellular Component (11): cytoplasm (GO:0005737), microvillus (GO:0005902), brush border (GO:0005903), filamentous actin (GO:0031941), stereocilium (GO:0032420), stereocilium tip (GO:0032426), cytoskeleton (GO:0005856), cell projection (GO:0042995), organelle (GO:0043226), actin-based cell projection (GO:0098858), cluster of actin-based cell projections (GO:0098862)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
actin-based cell projection	3
sensory perception of mechanical stimulus	1
microvillus assembly	1
parallel actin filament bundle assembly	1
cellular component assembly	1
actin filament bundle organization	1
protein domain specific binding	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
binding	1
intracellular anatomical structure	1
actin filament bundle	1
microvillus	1
apical part of cell	1
cluster of actin-based cell projections	1
actin filament	1
protein-containing complex	1
stereocilium bundle	1
neuron projection	1
stereocilium	1
intracellular membraneless organelle	1
actin cytoskeleton	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

1674 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESPN	FSCN1	Q16658	942
ESPN	MYO15A	Q9UKN7	841
ESPN	EPS8	Q12929	803
ESPN	WHRN	Q9P202	788
ESPN	GJB2	P29033	785
ESPN	MYO3A	Q8NEV4	749
ESPN	EPS8L2	Q9H6S3	744
ESPN	MYO7A	P78427	741
ESPN	STRC	Q7RTU9	711
ESPN	E9PNW1	E9PNW1	697
ESPN	MYO3B	Q8WXR4	673
ESPN	PLS1	Q14651	666
ESPN	BAIAP2	Q9UQB8	648
ESPN	CDH23	Q9H251	638
ESPN	TRIOBP	Q9H2D6	633

IntAct

10 interactions, top by confidence:

A	B	Type	Score
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
RAB37	ESPN	psi-mi:“MI:0914”(association)	0.350
DNAI1	ESPN	psi-mi:“MI:0914”(association)	0.350
ESPN	CTSC	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
UBXN6	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
BAIAP2	ESPN	psi-mi:“MI:0914”(association)	0.350
PNKD	ESPN	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): ESPN (Affinity Capture-RNA), ESPN (Affinity Capture-RNA), ESPN (Affinity Capture-MS), PRMT2 (Affinity Capture-MS), BAIAP2L1 (Affinity Capture-MS), CTSC (Affinity Capture-MS), BAIAP2 (Affinity Capture-MS), ESPN (Affinity Capture-MS), C17orf70 (Affinity Capture-MS), ESPN (Affinity Capture-MS), ESPN (Affinity Capture-MS), ESPN (Affinity Capture-MS), ESPN (Affinity Capture-MS), FAM98A (Affinity Capture-MS), ESPN (Affinity Capture-MS)

ESM2 similar proteins: A2AB59, B1AK53, B2DD29, D3YZU1, D3ZG83, O09039, O14976, O54967, O75427, P80192, P98171, Q02779, Q17R13, Q3TBD2, Q3U1V8, Q3UHC7, Q4ACU6, Q4LDD4, Q5DU25, Q5JU85, Q5RB40, Q5RJI5, Q5TCX8, Q5U2X5, Q5VWQ8, Q61097, Q61210, Q66HA1, Q66L42, Q6TLK4, Q6ZUM4, Q80XI6, Q86VW2, Q8IVT5, Q8R0S2, Q8R5F8, Q8R5G7, Q8TDC3, Q8TE68, Q8WWN8

Diamond homologs: B1AK53, Q3UYR4, Q63618, Q6ZVH7, Q9ET47

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

596 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	11
Uncertain significance	300
Likely benign	178
Benign	44

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1299307	NM_031475.3(ESPN):c.2081_2082del (p.Ser694fs)	Pathogenic
2445633	NM_031475.3(ESPN):c.2496C>G (p.Tyr832Ter)	Pathogenic
2572469	NM_031475.3(ESPN):c.1649_1665del (p.Arg550fs)	Pathogenic
3601083	NM_031475.3(ESPN):c.1916-1G>A	Pathogenic
3601084	NM_031475.3(ESPN):c.1995_2056del (p.Lys666fs)	Pathogenic
4291998	NM_031475.3(ESPN):c.489-2A>G	Pathogenic
4418	NM_031475.3(ESPN):c.2470_2473del (p.Ser824fs)	Pathogenic
4419	NM_031475.3(ESPN):c.1988_1991del (p.Lys663fs)	Pathogenic
4420	NM_031475.3(ESPN):c.2155A>C (p.Ser719Arg)	Pathogenic
4422	NM_031475.3(ESPN):c.2321G>A (p.Arg774Gln)	Pathogenic
4424	NM_031475.3(ESPN):c.1756dup (p.Ala586fs)	Pathogenic
560535	NM_031475.3(ESPN):c.2369_2386del (p.Arg790_Arg795del)	Pathogenic
594412	NM_031475.3(ESPN):c.264G>A (p.Trp88Ter)	Pathogenic
984702	NM_031475.3(ESPN):c.1916-1G>C	Pathogenic
1333558	NM_031475.3(ESPN):c.2524C>T (p.Arg842Ter)	Likely pathogenic
2445625	NM_031475.3(ESPN):c.1972G>A (p.Glu658Lys)	Likely pathogenic
3075865	NM_031475.3(ESPN):c.677del (p.Val226fs)	Likely pathogenic
3075897	NM_031475.3(ESPN):c.244dup (p.His82fs)	Likely pathogenic
3249455	NM_031475.3(ESPN):c.1464+2T>G	Likely pathogenic
3911751	NM_031475.3(ESPN):c.487_488+2del	Likely pathogenic
4081378	NM_031475.3(ESPN):c.2398del (p.Glu800fs)	Likely pathogenic
4423	NM_031475.3(ESPN):c.2539AAG[1] (p.Lys848del)	Likely pathogenic
450999	NM_031475.3(ESPN):c.1464+1G>A	Likely pathogenic
452503	NM_031475.3(ESPN):c.292C>T (p.Gln98Ter)	Likely pathogenic
623132	NM_031475.3(ESPN):c.2446G>T (p.Glu816Ter)	Likely pathogenic

SpliceAI

3102 predictions. Top by Δscore:

Variant	Effect	Δscore
1:6425247:CAGG:C	donor_loss	1.0000
1:6425250:G:GA	donor_loss	1.0000
1:6425251:T:G	donor_loss	1.0000
1:6428416:C:CG	donor_gain	1.0000
1:6428416:C:G	donor_gain	1.0000
1:6428418:GA:G	donor_gain	1.0000
1:6428420:G:GG	donor_gain	1.0000
1:6440248:CCGCA:C	acceptor_loss	1.0000
1:6440249:CGCA:C	acceptor_loss	1.0000
1:6440250:GCAG:G	acceptor_loss	1.0000
1:6440251:CA:C	acceptor_loss	1.0000
1:6440252:AG:A	acceptor_gain	1.0000
1:6440252:AGG:A	acceptor_gain	1.0000
1:6440253:GG:G	acceptor_gain	1.0000
1:6440253:GGG:G	acceptor_gain	1.0000
1:6440253:GGGGA:G	acceptor_gain	1.0000
1:6440614:C:A	acceptor_gain	1.0000
1:6440799:G:GT	donor_gain	1.0000
1:6440804:TAGAG:T	donor_loss	1.0000
1:6440805:AGAGG:A	donor_loss	1.0000
1:6440807:AGGTC:A	donor_loss	1.0000
1:6440808:GG:G	donor_loss	1.0000
1:6440809:G:T	donor_loss	1.0000
1:6440810:T:G	donor_loss	1.0000
1:6440930:GCAGT:G	acceptor_loss	1.0000
1:6440932:A:AG	acceptor_gain	1.0000
1:6440933:G:GC	acceptor_loss	1.0000
1:6440933:G:GG	acceptor_gain	1.0000
1:6440933:GT:G	acceptor_gain	1.0000
1:6441062:CCTGG:C	donor_loss	1.0000

AlphaMissense

5490 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:6452028:T:A	W753R	1.000
1:6452028:T:C	W753R	1.000
1:6452030:G:C	W753C	1.000
1:6452030:G:T	W753C	1.000
1:6440789:C:A	A280D	0.999
1:6452033:G:C	K754N	0.999
1:6452033:G:T	K754N	0.999
1:6460099:T:A	W840R	0.999
1:6460099:T:C	W840R	0.999
1:6460101:G:C	W840C	0.999
1:6460101:G:T	W840C	0.999
1:6440785:G:C	A279P	0.998
1:6440788:G:C	A280P	0.998
1:6440798:G:T	G283V	0.998
1:6452029:G:C	W753S	0.998
1:6452035:G:C	R755P	0.998
1:6440786:C:A	A279D	0.997
1:6440797:G:T	G283W	0.997
1:6440947:T:C	L291P	0.997
1:6441046:T:C	L324P	0.997
1:6440690:C:A	A247E	0.996
1:6440693:C:A	A248E	0.996
1:6440726:T:C	L259P	0.996
1:6452034:C:A	R755S	0.996
1:6440692:G:C	A248P	0.995
1:6440774:C:G	P275R	0.995
1:6440777:T:C	L276P	0.995
1:6440939:C:G	C288W	0.995
1:6441007:T:C	L311P	0.995
1:6441035:C:G	C320W	0.995

dbSNP variants (sampled 300 via entrez): RS1000105618 (1:6424691 G>A), RS1000130641 (1:6461260 T>G), RS1000132621 (1:6441457 T>C), RS1000238053 (1:6425670 G>A), RS1000394965 (1:6429351 T>C), RS1000471044 (1:6440161 T>C), RS1000526415 (1:6425404 T>C,G), RS1000542638 (1:6439797 C>A,G), RS1000750699 (1:6434259 C>G), RS1000816318 (1:6435489 C>T), RS1000826865 (1:6449799 C>A), RS1000935631 (1:6454702 G>A), RS1000971204 (1:6426889 A>C), RS1000976060 (1:6433910 T>C), RS1001033640 (1:6445267 G>A,T)

Disease associations

OMIM: gene MIM:606351 | disease phenotypes: MIM:609006, MIM:618632, MIM:609823, MIM:220290, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 36	Definitive	Autosomal recessive
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
Usher syndrome type 1	Supportive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
Usher syndrome, type 1M	Limited	Unknown

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AR
nonsyndromic genetic hearing loss	Limited	AD

Mondo (9): autosomal recessive nonsyndromic hearing loss 36 (MONDO:0012170), Usher syndrome, type 1M (MONDO:0032841), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), autosomal recessive nonsyndromic hearing loss 28 (MONDO:0012355), sensorineural hearing loss disorder (MONDO:0020678), Usher syndrome type 1 (MONDO:0010168), hearing loss, autosomal recessive (MONDO:0019588), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (6): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rare genetic deafness (Orphanet:96210), Usher syndrome type 1 (Orphanet:231169), Usher syndrome (Orphanet:886), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

22 total (23 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000375	Abnormal cochlea morphology
HP:0000399	Prelingual sensorineural hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000543	Optic disc pallor
HP:0000572	Visual loss
HP:0000575	Scotoma
HP:0000662	Nyctalopia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001270	Motor delay
HP:0001712	Left ventricular hypertrophy
HP:0001751	Abnormal vestibular function
HP:0002141	Gait imbalance
HP:0007663	Reduced visual acuity
HP:0007994	Peripheral visual field loss
HP:0008568	Vestibular areflexia
HP:0011510	Drusen
HP:0000556	Retinal dystrophy

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005116_11	Male-pattern baldness	8.000000e-10
GCST009597_70	Multiple sclerosis	9.000000e-17
GCST010151_1	Carotid intima media thickness x smoking interaction	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006527	smoking status measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
C564609	Deafness, Autosomal Recessive (supp.)
C565218	Deafness, Autosomal Recessive 28 (supp.)
C563815	Deafness, Autosomal Recessive 36 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, decreases methylation	4
Genistein	affects cotreatment, decreases expression, increases expression	4
bisphenol A	affects expression, increases expression	3
Air Pollutants	increases expression, decreases expression, increases abundance	3
Benzo(a)pyrene	decreases expression, increases methylation	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	increases expression	1
daidzein	decreases expression, affects cotreatment	1
methyleugenol	decreases expression	1
beta-lapachone	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	decreases methylation	1
glycitein	decreases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
licochalcone B	increases expression	1
Rosiglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Caffeine	increases phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diethylnitrosamine	decreases expression	1
Diethylstilbestrol	increases expression	1
Endosulfan	increases expression	1
Folic Acid	decreases expression	1
Lead	affects expression	1

Clinical trials (associated diseases)

138 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics