OTOF

Summary

OTOF (otoferlin, HGNC:8515) is a protein-coding gene on chromosome 2p23.3, encoding Otoferlin (Q9HC10). Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion and in the control of neurotransmitter release at these output synapses.

Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene.

Source: NCBI Gene 9381 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive nonsyndromic hearing loss 9 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 2,267 total — 202 pathogenic, 128 likely-pathogenic
• Phenotypes (HPO): 5
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_194248

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8515
Approved symbol	OTOF
Name	otoferlin
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	FER1L2, DFNB6
Ensembl gene	ENSG00000115155
Ensembl biotype	protein_coding
OMIM	603681
Entrez	9381

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000272371, ENST00000338581, ENST00000339598, ENST00000402415, ENST00000403946, ENST00000426958, ENST00000464574

RefSeq mRNA: 5 — MANE Select: NM_194248 NM_001287489, NM_004802, NM_194248, NM_194322, NM_194323

CCDS: CCDS1724, CCDS1725, CCDS1726, CCDS74497

Canonical transcript exons

ENST00000272371 — 47 exons

Exon	Start	End
ENSE00000730919	26477172	26477288
ENSE00000730924	26477416	26477506
ENSE00000809014	26474513	26474674
ENSE00000809016	26476891	26477043
ENSE00001035571	26473132	26473294
ENSE00001035576	26460647	26460747
ENSE00001035578	26463483	26463571
ENSE00001035581	26465949	26466076
ENSE00001035584	26472519	26472649
ENSE00001035590	26460008	26460205
ENSE00001035593	26473406	26473567
ENSE00001035595	26468408	26468474
ENSE00001035598	26467099	26467233
ENSE00001035600	26467365	26467501
ENSE00001035601	26470593	26470721
ENSE00001035605	26466714	26466851
ENSE00001035606	26471121	26471150
ENSE00001035614	26460852	26461030
ENSE00001078193	26462083	26462181
ENSE00001078195	26475914	26476038
ENSE00001078196	26473991	26474110
ENSE00001078197	26476128	26476317
ENSE00001078219	26475359	26475493
ENSE00001078221	26461696	26461937
ENSE00001593826	26489678	26489740
ENSE00001603455	26489211	26489295
ENSE00001605830	26527832	26527920
ENSE00001608807	26519010	26519109
ENSE00001618818	26482406	26482592
ENSE00001662115	26479264	26479384
ENSE00001667329	26483462	26483648
ENSE00001669380	26480203	26480311
ENSE00001698930	26503772	26503845
ENSE00001705015	26494942	26495073
ENSE00001733990	26516418	26516599
ENSE00001737499	26502300	26502426
ENSE00001761294	26480786	26481009
ENSE00001763591	26501754	26501808
ENSE00001778753	26537716	26537774
ENSE00001796469	26484474	26484633
ENSE00001802185	26479473	26479653
ENSE00002213997	26558493	26558756
ENSE00003486275	26463964	26464106
ENSE00003521398	26464869	26465029
ENSE00003543372	26477649	26477749
ENSE00003577110	26465672	26465842
ENSE00003900638	26457203	26458220

Expression profiles

Bgee: expression breadth ubiquitous, 109 present calls, max score 85.66.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2615 / max 35.0233, expressed in 70 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27428	0.1266	36
27427	0.0606	29
27423	0.0217	5
27422	0.0205	5
27425	0.0147	4
27424	0.0106	3
27421	0.0069	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	85.66	gold quality
putamen	UBERON:0001874	82.31	gold quality
caudate nucleus	UBERON:0001873	80.92	gold quality
quadriceps femoris	UBERON:0001377	72.08	gold quality
granulocyte	CL:0000094	66.11	gold quality
hypothalamus	UBERON:0001898	65.64	gold quality
thymus	UBERON:0002370	62.98	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	62.95	silver quality
temporal lobe	UBERON:0001871	61.57	gold quality
amygdala	UBERON:0001876	61.35	gold quality
prefrontal cortex	UBERON:0000451	60.57	gold quality
brain	UBERON:0000955	59.68	gold quality
ventricular zone	UBERON:0003053	58.76	gold quality
cerebellar vermis	UBERON:0004720	58.50	gold quality
frontal cortex	UBERON:0001870	58.00	gold quality
superior frontal gyrus	UBERON:0002661	57.84	gold quality
colonic epithelium	UBERON:0000397	57.80	gold quality
sural nerve	UBERON:0015488	55.91	gold quality
right adrenal gland cortex	UBERON:0035827	55.77	gold quality
cerebral cortex	UBERON:0000956	55.09	gold quality
skeletal muscle tissue	UBERON:0001134	54.91	gold quality
right adrenal gland	UBERON:0001233	54.71	gold quality
duodenum	UBERON:0002114	54.40	gold quality
right frontal lobe	UBERON:0002810	54.36	gold quality
cerebellum	UBERON:0002037	54.24	gold quality
cerebellar cortex	UBERON:0002129	54.21	gold quality
cerebellar hemisphere	UBERON:0002245	54.21	gold quality
gastrocnemius	UBERON:0001388	54.16	gold quality
right hemisphere of cerebellum	UBERON:0014890	54.15	gold quality
leukocyte	CL:0000738	53.94	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PGR

miRNA regulators (miRDB)

55 targeting OTOF, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-486-5P	99.51	70.39	707
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-940	99.37	66.14	2064

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• This publication deals with the otoferlin, which is related in sequence to FER1L4. (PMID:10192385)
• Q829X, a novel mutation in OTOF, is the third most frequent mutation causing prelingual non-syndromic hearing loss reported so far in the Spanish population. (PMID:12114484)
• Substitutions in the conserved Ca-binding C2C domain of otoferlin cause DFNB9, a form of nonsyndromic autosomal recessive deafness. 2 new mutations were found in exon 15 of the long splice form: 490 (Pro > Gln) and 515 (Ile > Thr. (PMID:12127154)
• There are uncommon cytidine-homopolymer dimorphisms in 5’-UTR of the human otoferlin gene. (PMID:12469219)
• Mutations in the OTOF gene cause a non-syndromic recessive auditory neuropathy. (PMID:12525542)
• Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy. (PMID:16371502)
• Otoferlin is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the auditory inner hair cell ribbon synapse. (PMID:17055430)
• OTOF does not seem to contribute to the pathogenesis of autosomal dominant auditory neuropathy in this family study. (PMID:18035737)
• Results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound nonsyndromic hearing impairment, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy. (PMID:18381613)
• Direct interaction of otoferlin with syntaxin 1A, SNAP-25, and the L-type voltage-gated calcium channel Cav1.3. (PMID:19004828)
• we demonstrate the existence of an alternative splice isoform of OTOF expressed in the human cochlea (PMID:19250381)
• Mutations in the OTOF gene are frequent causes of auditory neuropathy in Brazil and our results confirm that they are spread worldwide. (PMID:19461658)
• mechano-electrical transduction and cochlear amplification are normal in patients with OTOF mutations. Potentials are consistent with decreased neurotransmitter release resulting in abnormal dendritic activation and impairment of auditory nerve firing. (PMID:19636622)
• Purpose of this paper is to analyse OTOF gene in a series of subjects affected by auditory neuropathy. Genetic analysis identified five new mutations. (PMID:20211493)
• The predominance of the p.E1700Q mutation and the evidence of its founder effect indicate a distinct OTOF mutation spectrum in Taiwanese patients with auditory neuropathy. (PMID:20224275)
• This study revealed a novel mutation p.Glu1804del in exon 44 of OTOF. The mutation was found to be homozygous in the three patients and segregated with the temperature-dependent deafness within the family. (PMID:20230791)
• The mutatuion screening confirms that the OTOF gene contributes to auditory neuropathy and to termperature-sensitive auditory neuropathy. (PMID:20504331)
• OTOF and PJVK gene variants have a role in auditory neuropathy spectrum disorder in Chinese patients (PMID:21935370)
• nine different mutations of OTOF were detected(seven of them were novel)in Japanese patients with auditory neuropathy (PMID:22575033)
• The study concludes that OTOF mutations are not the major cause of autosomal recessive nonsyndromic hearing loss in the Iranian population. (PMID:22906306)
• Otoferlin is a multi-C2 domain protein associated with genetic human deafness. It functions in hair-cell exocytosis. Several otoferlin C2 domains bind to Ca2+, phospholipids, & proteins. Review. (PMID:22959777)
• Data indicate that dysferlin, otoferlin, and myoferlin do not merely passively adsorb to membranes but actively sculpt lipid bilayers. (PMID:23859474)
• OTOF gene mutataion is found in a Chinese patient with auditory neuropathy spectrum disorder. (PMID:24001616)
• The six probable pathogenic variants of OTOF genes were novel: 2 nonsense mutations (p.W717X, p.S1368X) and 4 missense mutations (p.D450E, p.R1583H, p.V1778I, p. E1803A). (PMID:24053799)
• We characterize a novel otoferlin mutation discovered in a sibling pair diagnosed with auditory neuropathy spectrum disorder and investigate auditory nerve function through their cochlear implants. (PMID:24135434)
• audiological phenotype associated with different OTOF mutations appears to be consistently different suggesting the presence of a genotype-phenotype correlation (PMID:24746455)
• Our observation of the discordant audiologic phenotype within the same DFNB9 family is more likely due to the loss of OAE over time rather than a genotype-phenotype correlation. (PMID:24814232)
• The C2F and C2C domains of otoferlin preferentially bind phosphatidylinositol 4,5-bisphosphate (4,5)P2. (PMID:24999532)
• three unrelated 2 to 6 year-old children who were diagnosed as auditory neuropathy patients who complained of severe hearing loss when they had fever had otoferlin (OTOF) homozygous or compound heterozygous mutations with the genotypes c.2975_2978delAG/c.4819C>T, c.4819C>T/c.4819C>T, or c.2382_2383delC/c.1621G>A (PMID:26778470)
• Our results confirmed that mutations in OTOF gene were a major cause of congenital Auditory neuropathy spectrum disorder (ANSD) in China. Identification of OTOF mutations can facilitate diagnosis, clinical intervention and counseling for congenital ANSD (PMID:26818607)
• Mutations in RAI1, OTOF, and SLC26A4 may have roles in nonsyndromic hearing loss in Altaian families in Siberia (PMID:27082237)
• The authors conclude that the TRC40 pathway is critical for hearing and propose that otoferlin is an essential substrate of this pathway in hair cells. (PMID:27458190)
• findings suggest that the mutation found in C2C domain of the OTOF gene is likely to cause deafness in the studied family reflecting the importance of C2 domains of otoferlin in hearing loss (PMID:27652356)
• In Otof(I515T/I515T) inner hair cells (IHCs), otoferlin levels are diminished by 65%, synaptic vesicles are enlarged, and exocytosis during prolonged stimulation is strongly reduced indicating that otoferlin is critical for the reformation of properly sized and fusion-competent synaptic vesicles. (PMID:27729456)
• Two mutations in the otoferlin gene, nonsense mutation p.R425X, contributes to a premature stop codon, may result in a truncated polypeptide, which strongly suggests its pathogenicity for auditory neuropathy spectrum disorder. The missense mutation p.L1665P results in a single amino acid substitution in a highly conserved region. (PMID:28335750)
• Although both otoferlin and synaptotagmin bind membrane fusion SNARE proteins, only otoferlin interacts with the L-type calcium channel Cav1.3. (PMID:28696301)
• ConclusionOur findings implicate OTOF as a potential major contributor to hearing loss in the Saudi population, while highlighting the low contribution of GJB2, thus offering important considerations for clinical testing strategies for Saudi patients. (PMID:29048421)
• This study suggested considerable genetic heterogeneity in the causation of hearing loss in Dhadkai. Recessive mutations were observed in at least three genes causing hearing loss: OTOF (p.R708X), SLC26A4 (p.Y556X) and CLDN14 (p.V85D). Mutation p.R708X appeared to be the major cause of hearing impairment in Dhadkai. (PMID:29434063)
• Results show that the FerA domain is a novel four-helix bundle fold with its own Ca(2+)-dependent phospholipid-binding activity which interaction with the membrane is enhanced by the presence of Ca(2+). (PMID:30026467)
• Three novel OTOF mutations (NM_001287489) [c.1550T > C (p.L517P), c.5900_5902delTCA (p.I1967del), and c.4669_4677delCTGACGGTG (p.L1557-V1559del)] were found to be the cause of hearing loss in five patients. (PMID:30073893)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	otofb	ENSDARG00000020581
danio_rerio	otofa	ENSDARG00000030832
mus_musculus	Otof	ENSMUSG00000062372
rattus_norvegicus	Otof	ENSRNOG00000009967
drosophila_melanogaster	mfr	FBGN0266757

Paralogs (4): DYSF (ENSG00000135636), MYOF (ENSG00000138119), FER1L6 (ENSG00000214814), FER1L5 (ENSG00000249715)

Protein

Protein identifiers

Otoferlin — Q9HC10 (reviewed: Q9HC10)

Alternative names: Fer-1-like protein 2

All UniProt accessions (3): Q9HC10, A0A2U3TZT7, H7BZJ5

UniProt curated annotations — full annotation on UniProt →

Function. Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion and in the control of neurotransmitter release at these output synapses. Interacts in a calcium-dependent manner to the presynaptic SNARE proteins at ribbon synapses of cochlear inner hair cells (IHCs) to trigger exocytosis of neurotransmitter. Also essential to synaptic exocytosis in immature outer hair cells (OHCs). May also play a role within the recycling of endosomes.

Subunit / interactions. Interacts with SNAP2; the interaction is direct. Interacts with STX1; the interaction is direct. Interacts with RAB8B.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Basolateral cell membrane. Endoplasmic reticulum membrane. Golgi apparatus membrane. Presynaptic cell membrane. Cell membrane. Golgi apparatus. trans-Golgi network.

Tissue specificity. Isoform 1 and isoform 3 are found in adult brain. Isoform 2 is expressed in the fetus and in adult brain, heart, placenta, skeletal muscle and kidney.

Disease relevance. Deafness, autosomal recessive, 9 (DFNB9) [MIM:601071] 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. The disease is caused by variants affecting the gene represented in this entry. Auditory neuropathy, autosomal recessive, 1 (AUNB1) [MIM:601071] A form of sensorineural hearing loss with absent or severely abnormal auditory brainstem response, in the presence of normal cochlear outer hair cell function and normal otoacoustic emissions. Auditory neuropathies result from a lesion in the area including the inner hair cells, connections between the inner hair cells and the cochlear branch of the auditory nerve, the auditory nerve itself and auditory pathways of the brainstem. In some cases AUNB1 phenotype can be temperature sensitive. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds Ca(2+). The ions are bound to the C2 1 domain.

Domain organisation. The N-terminal first 124 residues can be classified as C2 domain, based on their 3D-structure. They are not sufficient for calcium ion or phospholipid binding.

Similarity. Belongs to the ferlin family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9HC10-1	1, Long	yes
Q9HC10-2	2, Short-1
Q9HC10-3	3, Short-2
Q9HC10-4	4, Short-3
Q9HC10-5	5

RefSeq proteins (5): NP_001274418, NP_004793, NP_919224, NP_919303, NP_919304 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR012561	Ferlin_B-domain	Domain
IPR012968	FerIin_dom	Domain
IPR032362	Ferlin_C	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR037720	C2B_Ferlin	Domain
IPR037721	Ferlin	Family
IPR037722	C2C_Ferlin	Domain
IPR037723	C2D_Ferlin	Domain
IPR037724	C2E_Ferlin	Domain
IPR037725	C2F_Ferlin	Domain
IPR037726	C2A_Ferlin	Domain
IPR055072	Ferlin_DSRM	Domain

Pfam: PF00168, PF08150, PF08151, PF16165, PF22901

UniProt features (78 total): sequence variant 29, binding site 19, domain 7, compositionally biased region 6, splice variant 5, region of interest 4, sequence conflict 3, topological domain 2, chain 1, coiled-coil region 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HC10-F1	76.98	0.37

Functional residue map

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

Ligand- & substrate-binding residues (19): 976; 976; 982; 1038; 1038; 1040; 1040; 1046; 1508; 1508; 1514; 1563 …

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9609523	Insertion of tail-anchored proteins into the endoplasmic reticulum membrane
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea

MSigDB gene sets: 115 (showing top): RNGTGGGC_UNKNOWN, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_MEMBRANE_FUSION, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_EXOCYTOSIS, GOCC_TRANS_GOLGI_NETWORK, GOBP_REGULATION_OF_NEUROTRANSMITTER_TRANSPORT, GOBP_SECRETION, GOBP_SIGNAL_RELEASE, GOBP_SYNAPTIC_SIGNALING, GOBP_SENSORY_PERCEPTION, GOBP_MEMBRANE_ORGANIZATION

GO Biological Process (4): sensory perception of sound (GO:0007605), synaptic vesicle exocytosis (GO:0016079), regulation of neurotransmitter secretion (GO:0046928), membrane fusion (GO:0061025)

GO Molecular Function (2): calcium ion binding (GO:0005509), metal ion binding (GO:0046872)

GO Cellular Component (14): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), trans-Golgi network (GO:0005802), cytosol (GO:0005829), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), synaptic vesicle membrane (GO:0030672), presynaptic membrane (GO:0042734), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein localization	1
Sensory processing of sound	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	3
neurotransmitter secretion	2
presynapse	2
endomembrane system	2
intracellular membrane-bounded organelle	2
sensory perception of mechanical stimulus	1
regulated exocytosis	1
establishment of localization in cell	1
vesicle-mediated transport in synapse	1
synaptic vesicle cycle	1
signal release from synapse	1
modulation of chemical synaptic transmission	1
regulation of neurotransmitter transport	1
regulation of secretion by cell	1
membrane organization	1
metal ion binding	1
cation binding	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
Golgi apparatus subcompartment	1
basal plasma membrane	1
plasma membrane region	1
synaptic vesicle	1
exocytic vesicle membrane	1
synaptic membrane	1
membrane	1
cell periphery	1
intracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

1232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTOF	MYO6	Q9UM54	924
OTOF	CACNA1D	Q01668	908
OTOF	RAB8B	Q92930	902
OTOF	SLC26A4	O43511	899
OTOF	MYO15A	Q9UKN7	878
OTOF	GJB2	P29033	876
OTOF	CTBP2	P56545	874
OTOF	SYT2	Q8N9I0	840
OTOF	TMC1	Q8TDI8	829
OTOF	SYT1	P21579	816
OTOF	CDH23	Q9H251	815
OTOF	MYO7A	P78427	781
OTOF	PJVK	Q0ZLH3	734
OTOF	TMPRSS3	P57727	722
OTOF	STRC	Q7RTU9	721

IntAct

7 interactions, top by confidence:

A	B	Type	Score
OTOF	B2M	psi-mi:“MI:0915”(physical association)	0.400
OTOF	HMGB2	psi-mi:“MI:0915”(physical association)	0.400
OTOF	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
OTOF	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
OTOF	CCDC85C	psi-mi:“MI:0915”(physical association)	0.400
BTG3	OTOF	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): OTOF (Biochemical Activity), OTOF (Two-hybrid), OTOF (Proximity Label-MS), OTOF (Proximity Label-MS), OTOF (Proximity Label-MS), OTOF (Proximity Label-MS), CCDC85C (Affinity Capture-MS), OTOF (Affinity Capture-MS), OTOF (Affinity Capture-MS), OTOF (Reconstituted Complex), OTOF (Two-hybrid), TRMT1 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A8I3NFE2, A0FGR8, A0FGR9, A2AP18, A4IJ05, O08625, O08874, O15357, O75038, P51432, P70218, P70268, Q01970, Q12851, Q3TZZ7, Q3U7R1, Q4VX76, Q5DTI8, Q5FWL4, Q5M7N9, Q5R8Q5, Q5RAG2, Q5RCK6, Q5RJH2, Q61161, Q62807, Q63433, Q6DN12, Q6XYQ8, Q7ZWU7, Q812E4, Q86SS6, Q8K394, Q8TDW5, Q920M7, Q925C0, Q92918, Q99JE6, Q99N48, Q9BSJ8

Diamond homologs: A0JJX5, A1CQG2, A1ZBD6, A2QQ28, A3KGK3, A4IFJ5, A6QQP7, A8KBH6, B1WAZ6, B8N7E5, G0S9J5, O14065, O14795, O43581, O75131, O75923, O94812, P04409, P05126, P05128, P05129, P05696, P05771, P05772, P0C869, P0C871, P10102, P10829, P13677, P17252, P20444, P21521, P27715, P29101, P41823, P41885, P46097, P46935, P49147, P63318

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

2267 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	202
Likely pathogenic	128
Uncertain significance	457
Likely benign	1049
Benign	113

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1180669	NM_194248.3(OTOF):c.1981dup (p.Asp661fs)	Pathogenic
1185082	NM_194248.3(OTOF):c.2985C>A (p.Cys995Ter)	Pathogenic
1185578	NM_194248.3(OTOF):c.3049G>T (p.Glu1017Ter)	Pathogenic
1185579	NM_194248.3(OTOF):c.1392+1del	Pathogenic
1185627	NM_194248.3(OTOF):c.1364_1366delinsTTGC (p.Tyr455fs)	Pathogenic
1185651	NM_194248.3(OTOF):c.1962dup (p.Pro655fs)	Pathogenic
1202582	NM_194248.3(OTOF):c.4882C>A (p.Pro1628Thr)	Pathogenic
1377303	NM_194248.3(OTOF):c.1966dup (p.Arg656fs)	Pathogenic
1404884	NM_194248.3(OTOF):c.153_159dup (p.Ser54fs)	Pathogenic
1433377	NM_194248.3(OTOF):c.5531del (p.Leu1844fs)	Pathogenic
1457789	NM_194248.3(OTOF):c.1469del (p.Pro490fs)	Pathogenic
1459692	NC_000002.11:g.(?26706310)(26707521_?)del	Pathogenic
164835	NM_194248.3(OTOF):c.5203del (p.Arg1735fs)	Pathogenic
164841	NM_194248.3(OTOF):c.4799+1G>A	Pathogenic
1677282	NM_194248.3(OTOF):c.2406+4A>G	Pathogenic
1699487	NM_194248.3(OTOF):c.4885del (p.His1629fs)	Pathogenic
1703044	NM_194248.3(OTOF):c.2407-2del	Pathogenic
1703045	NM_194248.3(OTOF):c.5833del (p.Ile1945fs)	Pathogenic
1703047	NM_194248.3(OTOF):c.3592dup (p.Leu1198fs)	Pathogenic
1703050	NM_194248.3(OTOF):c.4110_4120dup (p.Lys1374fs)	Pathogenic
178509	NM_194248.3(OTOF):c.2991+2T>G	Pathogenic
179115	NM_194248.3(OTOF):c.3178del (p.Ala1060fs)	Pathogenic
179539	NM_194248.3(OTOF):c.2818C>T (p.Gln940Ter)	Pathogenic
179828	NM_194248.3(OTOF):c.2977_2978del (p.Gln994fs)	Pathogenic
1799530	NM_194248.3(OTOF):c.3192C>G (p.Tyr1064Ter)	Pathogenic
1956914	NM_194248.3(OTOF):c.4036C>T (p.Gln1346Ter)	Pathogenic
1972386	NM_194248.3(OTOF):c.1962del (p.Arg656fs)	Pathogenic
21825	NM_194248.3(OTOF):c.1651del (p.Glu551fs)	Pathogenic
21831	NM_194248.3(OTOF):c.2122C>T (p.Arg708Ter)	Pathogenic
21834	NM_194248.3(OTOF):c.2348del (p.Gly783fs)	Pathogenic

SpliceAI

9051 predictions. Top by Δscore:

Variant	Effect	Δscore
2:26458216:GCCGG:G	acceptor_gain	1.0000
2:26458217:CCGG:C	acceptor_gain	1.0000
2:26458217:CCGGC:C	acceptor_gain	1.0000
2:26458218:CGG:C	acceptor_gain	1.0000
2:26458218:CGGC:C	acceptor_gain	1.0000
2:26458219:GG:G	acceptor_gain	1.0000
2:26458221:C:CC	acceptor_gain	1.0000
2:26458228:G:C	acceptor_gain	1.0000
2:26458228:G:GC	acceptor_gain	1.0000
2:26460645:A:AC	donor_gain	1.0000
2:26460646:C:CC	donor_gain	1.0000
2:26460846:GCGCA:G	donor_loss	1.0000
2:26460847:CGCAC:C	donor_loss	1.0000
2:26460848:GCA:G	donor_loss	1.0000
2:26460849:CACC:C	donor_loss	1.0000
2:26460850:A:AT	donor_loss	1.0000
2:26460867:A:AC	donor_gain	1.0000
2:26460867:AT:A	donor_gain	1.0000
2:26460868:T:C	donor_gain	1.0000
2:26461678:C:A	donor_gain	1.0000
2:26461683:C:A	donor_gain	1.0000
2:26461727:AT:A	donor_gain	1.0000
2:26461728:T:TA	donor_gain	1.0000
2:26461729:C:A	donor_gain	1.0000
2:26461765:A:AC	donor_gain	1.0000
2:26461766:C:CC	donor_gain	1.0000
2:26462081:ACCC:A	donor_gain	1.0000
2:26462082:CCCC:C	donor_gain	1.0000
2:26462112:C:A	donor_gain	1.0000
2:26462177:CGTAC:C	acceptor_gain	1.0000

AlphaMissense

13181 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:26460735:C:G	A1909P	1.000
2:26460746:C:T	G1905D	1.000
2:26460896:A:G	W1890R	1.000
2:26460896:A:T	W1890R	1.000
2:26460899:A:G	W1889R	1.000
2:26460899:A:T	W1889R	1.000
2:26460901:C:T	G1888D	1.000
2:26460902:C:G	G1888R	1.000
2:26460972:G:C	C1864W	1.000
2:26460974:A:G	C1864R	1.000
2:26461696:C:A	G1845W	1.000
2:26461704:T:A	D1842V	1.000
2:26461728:T:G	D1834A	1.000
2:26461730:C:A	W1833C	1.000
2:26461730:C:G	W1833C	1.000
2:26461732:A:G	W1833R	1.000
2:26461732:A:T	W1833R	1.000
2:26461740:A:G	L1830P	1.000
2:26461746:A:G	L1828P	1.000
2:26461858:A:G	W1791R	1.000
2:26461858:A:T	W1791R	1.000
2:26461859:G:C	N1790K	1.000
2:26461859:G:T	N1790K	1.000
2:26461862:G:C	F1789L	1.000
2:26461862:G:T	F1789L	1.000
2:26461864:A:G	F1789L	1.000
2:26461870:C:G	G1787R	1.000
2:26462098:T:A	D1759V	1.000
2:26462170:C:G	R1735P	1.000
2:26462173:A:G	L1734P	1.000

dbSNP variants (sampled 300 via entrez): RS1000014103 (2:26468266 G>A), RS1000039684 (2:26499918 G>C), RS1000049117 (2:26525519 C>CA), RS1000114483 (2:26463653 T>C), RS1000122339 (2:26505440 C>G), RS1000139553 (2:26519593 A>G), RS1000151426 (2:26556153 C>A,T), RS1000171917 (2:26552456 A>G), RS1000179158 (2:26517119 G>A), RS1000181042 (2:26545191 A>C,G), RS1000184612 (2:26536345 G>A), RS1000229493 (2:26522296 T>C), RS1000261567 (2:26506399 C>T), RS1000272700 (2:26503398 A>G), RS1000292907 (2:26539695 A>G)

Disease associations

OMIM: gene MIM:603681 | disease phenotypes: MIM:601071, MIM:274600, MIM:128600, MIM:609129, MIM:220290, MIM:607197, MIM:601701, MIM:600316

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 9	Definitive	Unknown
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 9	Definitive	AR

Mondo (9): autosomal recessive nonsyndromic hearing loss 9 (MONDO:0010986), hearing loss disorder (MONDO:0005365), Pendred syndrome (MONDO:0010134), ear malformation (MONDO:0007500), auditory neuropathy (MONDO:0021944), hearing loss, autosomal recessive (MONDO:0019588), nonsyndromic genetic hearing loss (MONDO:0019497), tricho-oculo-dermo-vertebral syndrome (MONDO:0011131), autosomal recessive nonsyndromic hearing loss 3 (MONDO:0010860)

Orphanet (6): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Pendred syndrome (Orphanet:705), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare non-syndromic genetic deafness (Orphanet:87884), Rare genetic deafness (Orphanet:96210), OBSOLETE: Tricho-oculo-dermo-vertebral syndrome (Orphanet:3354)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0003577	Congenital onset
HP:0004463	Absent brainstem auditory responses
HP:0008529	Absence of acoustic reflex

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001588_13	Periodontal microbiota	2.000000e-06
GCST001823_2	Metabolite levels (HVA/MHPG ratio)	4.000000e-06
GCST001824_4	Metabolite levels (HVA)	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005131	HVA measurement
EFO:0005133	MHPG measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C537441	Arthrogryposis and ectodermal dysplasia (supp.)
C538268	Auditory neuropathy (supp.)
C564609	Deafness, Autosomal Recessive (supp.)
C563961	Deafness, Autosomal Recessive 3 (supp.)
C580334	Nonsyndromic Deafness (supp.)
C536648	Pendred syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases mutagenesis	3
Estradiol	affects binding, increases expression, affects expression, increases reaction	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
methylparaben	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
butylparaben	increases expression	1
abrine	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects expression	1
Arsenic	affects methylation	1
Cisplatin	affects expression	1
Copper	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Methapyrilene	increases methylation	1
Rotenone	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	affects expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT05402813	Not specified	RECRUITING	Natural History in Children up to 16 Years With Mild to Profound Hearing Loss Due to Mutations in GJB2 / OTOF Genes
NCT05901480	Not specified	UNKNOWN	An Investigator Initiated Study for OTOV101N+OTOV101C Injection
NCT06722170	Not specified	RECRUITING	A Study of EH002 Gene Therapy for Otoferlin Gene Mutation-mediated Hearing Loss
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss