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.
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]
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]
^"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.
PMID10192385.
S2CID19269361.
^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.
PMID21216247.
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.
PMID10843812.
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.
PMID12127154.
S2CID37646982.
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.
PMID12469219.