Otoferlin

Protein-coding gene in the species Homo sapiens

OTOF

Identifiers

Aliases

OTOF, AUNB1, DFNB6, DFNB9, FER1L2, NSRD9, otoferlin

External IDs

OMIM: 603681 MGI: 1891247 HomoloGene: 12892 GeneCards: OTOF

Gene location (Human)

Chr.	Chromosome 2 (human)^[1]

Band	2p23.3	Start	26,457,203 bp^[1]
Band	2p23.3	End	26,558,756 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 5 (mouse)^[2]

Band	5\|5 B1	Start	30,524,406 bp^[2]
Band	5\|5 B1	End	30,619,276 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

nucleus accumbens

putamen

caudate nucleus

hypothalamus

temporal lobe

amygdala

prefrontal cortex

superior frontal gyrus

skeletal muscle tissue

duodenum

Top expressed in

utricle

olfactory tubercle

molar

superior frontal gyrus

neuron

right ventricle

saccule

nucleus accumbens

temporal lobe

cochlea

More reference expression data

BioGPS


More reference expression data

Gene ontology
Molecular function	calcium ion binding molecular function
Cellular component	integral component of membrane cytosol cell junction plasma membrane basolateral plasma membrane synapse synaptic vesicle membrane endoplasmic reticulum membrane endoplasmic reticulum membrane cytoplasmic vesicle
Biological process	membrane fusion sensory perception of sound synaptic vesicle exocytosis
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

Entrez


9381


83762

Ensembl


ENSG00000115155


ENSMUSG00000062372

UniProt


Q9HC10


Q9ESF1

RefSeq (mRNA)


NM_001287489 NM_004802 NM_194248 NM_194322 NM_194323


NM_001100395 NM_001286421 NM_031875 NM_001313767

RefSeq (protein)


NP_001274418 NP_004793 NP_919224 NP_919303 NP_919304


NP_001093865 NP_001273350 NP_001300696 NP_114081

Location (UCSC)

Chr 2: 26.46 – 26.56 Mb

Chr 5: 30.52 – 30.62 Mb

PubMed search

^[3]

^[4]

Wikidata

View/Edit Human

View/Edit Mouse

Otoferlin is a protein that in humans is encoded by the OTOF gene.^[5]^[6]^[7] It is involved in vesicle membrane fusion, and mutations in the OTOF gene are associated with a genetic form of deafness.

Function

There are two forms of otoferlin protein. The short form of the protein has three C2 domains and a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin. The long form has six C2 domains.

Dysferlin and myoferlin are proteins found in humans that are homologous to otoferlin. Both dysferlin and myoferlin have seven C2 domains. A C2 domain is a protein structural domain involved in targeting proteins to cell membranes.

C2A in otoferlin's longer form, with six C2 domains, is structurally similar to dysferlin C2A. However, loop 1 in the calcium (Ca²⁺) binding site of otoferlin C2A is significantly shorter than the homologous loop in dysferlin and myoferlin C2A domains. Therefore, it is unable to bind to calcium. Otoferlin C2A is also unable to bind to phospholipids and hence it is structurally and functionally distinct from other C2 domains.^[8] Nonetheless, the homology suggests that this protein may be involved in vesicle membrane fusion.

Similar to dysferlin and myoferlin, otoferlin has a FerA domain and its FerA domain has been shown to interact with zwitterionic lipids in a calcium-dependent manner and with negatively charged lipids in a calcium-independent manner.^[9] The estimated charge of the FerA domain among ferlin proteins varies significantly. At pH 7, the estimated charge of dysferlin is -8.4 while otoferlin FerA is +8.5.^[9] Several transcript variants encoding multiple isoforms have been found for this gene.^[7]

Role in deafness

Mutations in the gene encoding otoferlin are a cause of a neurosensory nonsyndromic recessive deafness, DFNB9. The diagnosis is identified by molecular genetic testing.

In October 2023 two small clinical trials for a gene therapy restoring the defective Otoferlin via an adeno-associated virus (AAVs) have been announced. The two experimental gene therapies are AAVAnc80-hOTOF and DB-OTO.^[10]^[11]A successful application of the therapy in Britain was announced in May 2024.^[12] ^[13]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000115155 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000062372 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Yasunaga S, Grati M, Cohen-Salmon M, El-Amraoui A, Mustapha M, Salem N, El-Zir E, Loiselet J, Petit C (April 1999). "A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness". Nature Genetics. 21 (4): 363–9. doi:10.1038/7693. PMID 10192385. S2CID 19269361.
^ Rodríguez-Ballesteros M, Reynoso R, Olarte M, Villamar M, Morera C, Santarelli R, Arslan E, Medá C, Curet C, Völter C, Sainz-Quevedo M, Castorina P, Ambrosetti U, Berrettini S, Frei K, Tedín S, Smith J, Cruz Tapia M, Cavallé L, Gelvez N, Primignani P, Gómez-Rosas E, Martín M, Moreno-Pelayo MA, Tamayo M, Moreno-Barral J, Moreno F, del Castillo I (June 2008). "A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy". Human Mutation. 29 (6): 823–31. doi:10.1002/humu.20708. PMID 18381613. S2CID 19170712.
^ ^a ^b "Entrez Gene: OTOF otoferlin".
^ Helfmann S, Neumann P, Tittmann K, Moser T, Ficner R, Reisinger E (February 2011). "The crystal structure of the C₂A domain of otoferlin reveals an unconventional top loop region". Journal of Molecular Biology. 406 (3): 479–90. doi:10.1016/j.jmb.2010.12.031. PMID 21216247.
^ ^a ^b Harsini FM, Chebrolu S, Fuson KL, White MA, Rice AM, Sutton RB (July 2018). "FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins". Scientific Reports. 8 (1): 10949. Bibcode:2018NatSR...810949H. doi:10.1038/s41598-018-29184-1. PMC 6053371. PMID 30026467.
^ "Some deaf children in China can hear after gene therapy treatment". MIT Technology Review. Retrieved 2023-11-09.
^ "REGENERON SHARES PRELIMINARY RESULTS SHOWING GENE THERAPY IMPROVES AUDITORY RESPONSES IN CHILD WITH PROFOUND GENETIC HEARING LOSS". Regeneron Pharmaceuticals. 26 October 2023.
^ "Pioneering gene therapy restores UK girl's hearing". BBC News. Retrieved 2024-05-09.
^ "UK toddler has hearing restored in world-first gene therapy trial". the Guardian. Retrieved 2024-05-09.

External links

GeneReviews/NCBI/NIH/UW entry on OTOF-Related Deafness

Fukushima K, Ramesh A, Srisailapathy CR, Ni L, Wayne S, O'Neill ME, Van Camp G, Coucke P, Jain P, Wilcox ER, Smith SD, Kenyon JB, Zbar RI, Smith RJ (October 1995). "An autosomal recessive nonsyndromic form of sensorineural hearing loss maps to 3p-DFNB6". Genome Research. 5 (3): 305–8. doi:10.1101/gr.5.3.305. PMID 8593615.
Yasunaga S, Petit C (May 2000). "Physical map of the region surrounding the OTOFERLIN locus on chromosome 2p22-p23". Genomics. 66 (1): 110–2. doi:10.1006/geno.2000.6185. PMID 10843812.
Adato A, Raskin L, Petit C, Bonne-Tamir B (June 2000). "Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus". European Journal of Human Genetics. 8 (6): 437–42. doi:10.1038/sj.ejhg.5200489. PMID 10878664.
Yasunaga S, Grati M, Chardenoux S, Smith TN, Friedman TB, Lalwani AK, Wilcox ER, Petit C (September 2000). "OTOF encodes multiple long and short isoforms: genetic evidence that the long ones underlie recessive deafness DFNB9". American Journal of Human Genetics. 67 (3): 591–600. doi:10.1086/303049. PMC 1287519. PMID 10903124.
Migliosi V, Modamio-Høybjør S, Moreno-Pelayo MA, Rodríguez-Ballesteros M, Villamar M, Tellería D, Menéndez I, Moreno F, Del Castillo I (July 2002). "Q829X, a novel mutation in the gene encoding otoferlin (OTOF), is frequently found in Spanish patients with prelingual non-syndromic hearing loss". Journal of Medical Genetics. 39 (7): 502–6. doi:10.1136/jmg.39.7.502. PMC 1735186. PMID 12114484.
Mirghomizadeh F, Pfister M, Apaydin F, Petit C, Kupka S, Pusch CM, Zenner HP, Blin N (July 2002). "Substitutions in the conserved C2C domain of otoferlin cause DFNB9, a form of nonsyndromic autosomal recessive deafness". Neurobiology of Disease. 10 (2): 157–64. doi:10.1006/nbdi.2002.0488. PMID 12127154. S2CID 37646982.
Mirghomizadeh F, Pfister M, Blin N, Pusch CM (January 2003). "Uncommon cytidine-homopolymer dimorphism in 5'-UTR of the human otoferlin gene". International Journal of Molecular Medicine. 11 (1): 63–4. doi:10.3892/ijmm.11.1.63. PMID 12469219.
Varga R, Kelley PM, Keats BJ, Starr A, Leal SM, Cohn E, Kimberling WJ (January 2003). "Non-syndromic recessive auditory neuropathy is the result of mutations in the otoferlin (OTOF) gene". Journal of Medical Genetics. 40 (1): 45–50. doi:10.1136/jmg.40.1.45. PMC 1735255. PMID 12525542.
Piechotta K, Garbarini N, England R, Delpire E (December 2003). "Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2Cl- cotransporter in the nervous system: evidence for a scaffolding role of the kinase". The Journal of Biological Chemistry. 278 (52): 52848–56. doi:10.1074/jbc.M309436200. PMID 14563843.
Varga R, Avenarius MR, Kelley PM, Keats BJ, Berlin CI, Hood LJ, Morlet TG, Brashears SM, Starr A, Cohn ES, Smith RJ, Kimberling WJ (July 2006). "OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele". Journal of Medical Genetics. 43 (7): 576–81. doi:10.1136/jmg.2005.038612. PMC 2593030. PMID 16371502.
Roux I, Safieddine S, Nouvian R, Grati M, Simmler MC, Bahloul A, Perfettini I, Le Gall M, Rostaing P, Hamard G, Triller A, Avan P, Moser T, Petit C (October 2006). "Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse". Cell. 127 (2): 277–89. doi:10.1016/j.cell.2006.08.040. PMID 17055430. S2CID 15233556.