Wikipedia

Otoferlin

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.

OTOF
Identifiers
AliasesOTOF, AUNB1, DFNB6, DFNB9, FER1L2, NSRD9, otoferlin
External IDsOMIM: 603681; MGI: 1891247; HomoloGene: 12892; GeneCards: OTOF; OMA:OTOF - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 5: 30.52 – 30.62 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000115155 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000062372 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ 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.
  7. ^ a b "Entrez Gene: OTOF otoferlin".
  8. ^ 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.
  9. ^ 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.
  10. ^ "Some deaf children in China can hear after gene therapy treatment". MIT Technology Review. Retrieved 2023-11-09.
  11. ^ "REGENERON SHARES PRELIMINARY RESULTS SHOWING GENE THERAPY IMPROVES AUDITORY RESPONSES IN CHILD WITH PROFOUND GENETIC HEARING LOSS". Regeneron Pharmaceuticals. 26 October 2023.
  12. ^ "Pioneering gene therapy restores UK girl's hearing". BBC News. Retrieved 2024-05-09.
  13. ^ "UK toddler has hearing restored in world-first gene therapy trial". the Guardian. Retrieved 2024-05-09.
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Further reading

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