Otoferlin

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

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) Band 2p23.3 Start 26,457,203 bp End 26,558,756 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5|5 B1 Start 30,524,406 bp End 30,619,276 bp
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
Wikidata
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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. 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.

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.