Otoferlin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''OTOF''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. It is involved in vesicle membrane fusion, and mutations in the OTOF gene are associated with a genetic form of

deafness Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is writte ...

Function

There are two forms of otoferlin protein. The short form of the protein has three

C2 domain A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 β-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by th ...

s and a single

carboxy-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

transmembrane domain A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...

found also in the ''

C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...

'' 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

s. A C2 domain is a

structural domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

involved in targeting proteins to

cell membranes The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extra ...

. 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

phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

s 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 In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively and negatively charged functional groups. : (1,2-dipolar compounds, such as ylides, are sometimes excluded from t ...

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 Transcript may refer to: * Transcript (biology), a molecule of RNA transcribed from DNA * Transcript (education), a copy of a student's permanent academic record * Transcript (law), a written record of spoken language in court proceedings * Transc ...

variants encoding multiple

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

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 Adeno-associated viruses (AAV) are small viruses that infect humans and some other primate species. They belong to the genus '' Dependoparvovirus'', which in turn belongs to the family ''Parvoviridae''. They are small (approximately 26 nm in ...

(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.

References

External links

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

Function

Role in deafness

References

External links

Further reading