A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness


Using a candidate gene approach, we identified a novel human gene, OTOF, underlying an autosomal recessive, nonsyndromic prelingual deafness, DFNB9. The same nonsense mutation was detected in four unrelated affected families of Lebanese origin. OTOF is the second member of a mammalian gene family related to Caenorhabditis elegans fer-1. It encodes a predicted cytosolic protein (of 1,230 aa) with three C2 domains and a single carboxy-terminal transmembrane domain. The sequence homologies and predicted structure of otoferlin, the protein encoded by OTOF, suggest its involvement in vesicle membrane fusion. In the inner ear, the expression of the orthologous mouse gene, mainly in the sensory hair cells, indicates that such a role could apply to synaptic vesicles.

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Figure 1: Genetic linkage analysis of the DFNB9-affected family AB.
Figure 2: Physical map of the DFNB9 region.
Figure 3: Sequence and structure of human otoferlin.
Figure 4: Sequence analysis of the mutation present in OTOF exon 18 in family F.
Figure 5: RT-PCR analysis of Otof expression in mouse tissues.
Figure 6: In situ hybridization analysis of Otof expression in mouse inner ear.

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We thank the families for participation; D. Weil for helpful advice; and J.-P. Hardelin and J. Levilliers for critical reading of the manuscript. This work was supported by grants from AFM, Association Entendre (France), Université Saint Joseph (Lebanon) and EEC (BMH4-CT-96). M.G. was supported by DGRST (Tunisia) and AFM.

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Correspondence to Christine Petit.

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