Otoferlin

Otoferlin is a protein that in humans is encoded by the OTOF gene. 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. 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. 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. Several transcript variants encoding multiple isoforms have been found for this gene.

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. A successful application of the therapy in Britain was announced in May 2024.