A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy

Montserrat Rodríguez-Ballesteros, Raúl Reynoso, Margarita Olarte, Manuela Villamar, Constantino Morera, Rosamaria Santarelli, Edoardo Arslan, Carme Medá, Carlos Curet, Christiane Völter, Manuel Sainz-Quevedo, Pierangela Castorina, Umberto Ambrosetti, Stefano Berrettini, Klemens Frei, Socorro Tedín, Janine Smith, M. Cruz Tapia, Laura Cavallé, Nancy GelvezPaola Primignani, Elena Gómez-Rosas, Mirta Martín, Miguel A. Moreno-Pelayo, Martalucía Tamayo, José Moreno-Barral, Felipe Moreno, Ignacio Del Castillo

Research output: Contribution to journalArticle

Abstract

Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy.

Original languageEnglish
Pages (from-to)823-831
Number of pages9
JournalHuman Mutation
Volume29
Issue number6
DOIs
Publication statusPublished - Jun 2008

Keywords

  • Auditory neuropathy
  • DFNB9
  • Genetic epidemiology
  • Hearing impairment
  • OTOF
  • Otoferlin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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  • Cite this

    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., Tapia, M. C., Cavallé, L., ... Del Castillo, I. (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), 823-831. https://doi.org/10.1002/humu.20708