Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has three C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has six C2 domains. Otoferlin homologous proteins in humans that have been shown to be associated with human diseases are dysferlin and myoferlin. Both dysferlin and myoferlin have seven C2 domains. C2A in otoferlin's longer form with six C2 domains is structurally similar to dysferlin C2A. However, the loop 1 in calcium 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 different from other C2 domains.[4] 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.[5] The estimated charge of FerA domain among ferlin proteins varies significantly. At pH 7, the estimated charge of dysferlin is -8.4 while otoferlin FerA is +8.5.[5] Several transcript variants encoding multiple isoforms have been found for this gene.[3]
↑Rodríguez-Ballesteros M, Reynoso R, Olarte M, Villamar M, Morera C, Santarelli R, Arslan E, Medá C, Curet C, Völter C, Sainz-Quevedo M, Castorina P, Ambrosetti U, Berrettini S, Frei K, Tedín S, Smith J, Cruz Tapia M, Cavallé L, Gelvez N, Primignani P, Gómez-Rosas E, Martín M, Moreno-Pelayo MA, Tamayo M, Moreno-Barral J, Moreno F, del Castillo I (June 2008). "A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy". Human Mutation. 29 (6): 823–31. doi:10.1002/humu.20708. PMID18381613.
↑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.
↑ 5.05.1Harsini FM, Chebrolu S, Fuson KL, White MA, Rice AM, Sutton RB (July 2018). "FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins". Scientific Reports. 8 (1): 10949. doi:10.1038/s41598-018-29184-1. PMID30026467.
Fukushima K, Ramesh A, Srisailapathy CR, Ni L, Wayne S, O'Neill ME, Van Camp G, Coucke P, Jain P, Wilcox ER, Smith SD, Kenyon JB, Zbar RI, Smith RJ (October 1995). "An autosomal recessive nonsyndromic form of sensorineural hearing loss maps to 3p-DFNB6". Genome Research. 5 (3): 305–8. doi:10.1101/gr.5.3.305. PMID8593615.
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.
Adato A, Raskin L, Petit C, Bonne-Tamir B (June 2000). "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". European Journal of Human Genetics. 8 (6): 437–42. doi:10.1038/sj.ejhg.5200489. PMID10878664.
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.
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.
Piechotta K, Garbarini N, England R, Delpire E (December 2003). "Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2Cl- cotransporter in the nervous system: evidence for a scaffolding role of the kinase". The Journal of Biological Chemistry. 278 (52): 52848–56. doi:10.1074/jbc.M309436200. PMID14563843.
Roux I, Safieddine S, Nouvian R, Grati M, Simmler MC, Bahloul A, Perfettini I, Le Gall M, Rostaing P, Hamard G, Triller A, Avan P, Moser T, Petit C (October 2006). "Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse". Cell. 127 (2): 277–89. doi:10.1016/j.cell.2006.08.040. PMID17055430.
