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Gene Review

OTOF  -  otoferlin

Homo sapiens

Synonyms: AUNB1, DFNB6, DFNB9, FER1L2, Fer-1-like protein 2, ...
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Disease relevance of OTOF

  • Hearing impairment was caused in one family by a novel mutation in the recently identified OTOF (the DFNB9 gene), by a novel Pendred syndrome mutation (Thr193Ile) in another family, and by a GJB2 mutation (35delG also known as 30delG) in the third family [1].

High impact information on OTOF

  • Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse [2].
  • Otoferlin binds Ca(2+) and displays Ca(2+)-dependent interactions with the SNARE proteins syntaxin1 and SNAP25 [2].
  • In this issue, demonstrate that otoferlin interacts with SNARE molecules at the afferent synapses of cochlear inner hair cells to trigger exocytosis of neurotransmitter [3].
  • We studied otoferlin, a predicted C2-domain transmembrane protein, which is defective in a recessive form of human deafness [2].
  • Thus, otoferlin is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the IHC ribbon synapse [2].

Biological context of OTOF

  • By SSCP analysis and DNA sequencing of the 48 exons of the DFNB9 gene, coding for otoferlin, previously reported mutations in OTOF were excluded [4].
  • Next to a frequent T > C single nucleotide polymorphism in exon 8, two novel mutations linked in exon 15 of the OTOF long splice form were identified comprising substitutions at positions 490 (Pro > Gln) and 515 (Ile > Thr), both located in the conserved Ca(2+) binding C2C domain of this peptide [4].
  • The autosomal recessive form of nonsyndromic deafness DFNB9 has been mapped to a 2-cM region on chromosome 2p22-p23, and the responsible gene, OTOF, has been recently identified by positional cloning combined with a candidate gene approach [5].
  • Nonsense and missense mutations of OTOF lead to an autosomal recessive deafness phenotype (DFNB9) [6].
  • The polymorphic site may become useful for studying the origin of different OTOF mutations within various populations, for assessing recombination events within large pedigrees as well as founder effects and for association studies in further deafness phenotypes [6].

Anatomical context of OTOF

  • Mutations in OTOF lead to inner hair cells dysfunction, whereas the outer hair cells are initially functionally preserved [7].
  • We have identified five different homozygous recessive mutations in a novel gene, TMIE (transmembrane inner ear expressed gene), in affected members of consanguineous families segregating severe-to-profound prelingual deafness, consistent with linkage to DFNB6 [8].
  • Consistent with a conserved role for this gene in the cochlea, the genetic mapping data presented here support human TMIE as the gene affected at DFNB6, a non-syndromic hearing loss locus [9].
  • Human otoferlin, homologous to the Caenorhabditis elegans spermatogenesis factor FER-1 that was shown to be involved in membrane vesicle fusion, belongs to a group of membrane-anchored cytosolic proteins and is found expressed in brain, cochlear inner hair cells and vestibular type I sensory cells [6].
  • We show that otoferlin expression in the hair cells correlates with afferent synaptogenesis and find that otoferlin localizes to ribbon-associated synaptic vesicles [2].

Associations of OTOF with chemical compounds

  • A novel missense mutation in a C2 domain of OTOF results in autosomal recessive auditory neuropathy [10].
  • Both parents were heterozygous for the mutation. p.Leu1011Pro alters a conserved leucine residue in the C2D domain of otoferlin [10].

Other interactions of OTOF


Analytical, diagnostic and therapeutic context of OTOF


  1. Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus. Adato, A., Raskin, L., Petit, C., Bonne-Tamir, B. Eur. J. Hum. Genet. (2000) [Pubmed]
  2. Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Roux, I., Safieddine, S., Nouvian, R., Grati, M., Simmler, M.C., Bahloul, A., Perfettini, I., Le Gall, M., Rostaing, P., Hamard, G., Triller, A., Avan, P., Moser, T., Petit, C. Cell (2006) [Pubmed]
  3. Snaring Otoferlin's Role in Deafness. Roberts, W.M. Cell (2006) [Pubmed]
  4. Substitutions in the conserved C2C domain of otoferlin cause DFNB9, a form of nonsyndromic autosomal recessive deafness. Mirghomizadeh, F., Pfister, M., Apaydin, F., Petit, C., Kupka, S., Pusch, C.M., Zenner, H.P., Blin, N. Neurobiol. Dis. (2002) [Pubmed]
  5. Physical map of the region surrounding the OTOFERLIN locus on chromosome 2p22-p23. Yasunaga, S., Petit, C. Genomics (2000) [Pubmed]
  6. Uncommon cytidine-homopolymer dimorphism in 5'-UTR of the human otoferlin gene. Mirghomizadeh, F., Pfister, M., Blin, N., Pusch, C.M. Int. J. Mol. Med. (2003) [Pubmed]
  7. Auditory neuropathy or endocochlear hearing loss? Loundon, N., Marcolla, A., Roux, I., Rouillon, I., Denoyelle, F., Feldmann, D., Marlin, S., Garabedian, E.N. Otol. Neurotol. (2005) [Pubmed]
  8. Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. Naz, S., Giguere, C.M., Kohrman, D.C., Mitchem, K.L., Riazuddin, S., Morell, R.J., Ramesh, A., Srisailpathy, S., Deshmukh, D., Riazuddin, S., Griffith, A.J., Friedman, T.B., Smith, R.J., Wilcox, E.R. Am. J. Hum. Genet. (2002) [Pubmed]
  9. Mutation of the novel gene Tmie results in sensory cell defects in the inner ear of spinner, a mouse model of human hearing loss DFNB6. Mitchem, K.L., Hibbard, E., Beyer, L.A., Bosom, K., Dootz, G.A., Dolan, D.F., Johnson, K.R., Raphael, Y., Kohrman, D.C. Hum. Mol. Genet. (2002) [Pubmed]
  10. A novel missense mutation in a C2 domain of OTOF results in autosomal recessive auditory neuropathy. Tekin, M., Akcayoz, D., Incesulu, A. Am. J. Med. Genet. A (2005) [Pubmed]
  11. OTOF encodes multiple long and short isoforms: genetic evidence that the long ones underlie recessive deafness DFNB9. Yasunaga, S., Grati, M., Chardenoux, S., Smith, T.N., Friedman, T.B., Lalwani, A.K., Wilcox, E.R., Petit, C. Am. J. Hum. Genet. (2000) [Pubmed]
  12. A novel locus for Usher syndrome type II, USH2B, maps to chromosome 3 at p23-24.2. Hmani, M., Ghorbel, A., Boulila-Elgaied, A., Ben Zina, Z., Kammoun, W., Drira, M., Chaabouni, M., Petit, C., Ayadi, H. Eur. J. Hum. Genet. (1999) [Pubmed]
  13. The third human FER-1-like protein is highly similar to dysferlin. Britton, S., Freeman, T., Vafiadaki, E., Keers, S., Harrison, R., Bushby, K., Bashir, R. Genomics (2000) [Pubmed]
  14. DFNB9 and DFNB12. Yasunaga, S., Grati, M., Petit, C. Adv. Otorhinolaryngol. (2000) [Pubmed]
  15. Results of cochlear implantation in two children with mutations in the OTOF gene. Rouillon, I., Marcolla, A., Roux, I., Marlin, S., Feldmann, D., Couderc, R., Jonard, L., Petit, C., Denoyelle, F., Garabédian, E.N., Loundon, N. Int. J. Pediatr. Otorhinolaryngol. (2006) [Pubmed]
  16. Differential expression of otoferlin in brain, vestibular system, immature and mature cochlea of the rat. Schug, N., Braig, C., Zimmermann, U., Engel, J., Winter, H., Ruth, P., Blin, N., Pfister, M., Kalbacher, H., Knipper, M. Eur. J. Neurosci. (2006) [Pubmed]
  17. Fine mapping of the circling (cir) gene on the distal portion of mouse chromosome 9. Cho, K.I., Lee, J.W., Kim, K.S., Lee, E.J., Suh, J.G., Lee, H.J., Kim, H.T., Hong, S.H., Chung, W.H., Chang, K.T., Hyun, B.H., Oh, Y.S., Ryoo, Z.Y. Comp. Med. (2003) [Pubmed]
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