title: A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy.
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.
authors.affiliation: Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rodríguez-Ballesteros
authors.forename: Raúl
authors.initials: R
authors.lastname: Reynoso
authors.forename: Margarita
authors.initials: M
authors.lastname: Olarte
authors.forename: Manuela
authors.initials: M
authors.lastname: Villamar
authors.forename: Constantino
authors.initials: C
authors.lastname: Morera
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Santarelli
authors.forename: Edoardo
authors.initials: E
authors.lastname: Arslan
authors.forename: Carme
authors.initials: C
authors.lastname: Medá
authors.forename: Carlos
authors.initials: C
authors.lastname: Curet
authors.forename: Christiane
authors.initials: C
authors.lastname: Völter
authors.forename: Manuel
authors.initials: M
authors.lastname: Sainz-Quevedo
authors.forename: Pierangela
authors.initials: P
authors.lastname: Castorina
authors.forename: Umberto
authors.initials: U
authors.lastname: Ambrosetti
authors.forename: Stefano
authors.initials: S
authors.lastname: Berrettini
authors.forename: Klemens
authors.initials: K
authors.lastname: Frei
authors.forename: Socorro
authors.initials: S
authors.lastname: Tedín
authors.forename: Janine
authors.initials: J
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Cruz Tapia
authors.forename: Laura
authors.initials: L
authors.lastname: Cavallé
authors.forename: Nancy
authors.initials: N
authors.lastname: Gelvez
authors.forename: Paola
authors.initials: P
authors.lastname: Primignani
authors.forename: Elena
authors.initials: E
authors.lastname: Gómez-Rosas
authors.forename: Mirta
authors.initials: M
authors.lastname: Martín
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Moreno-Pelayo
authors.forename: Martalucía
authors.initials: M
authors.lastname: Tamayo
authors.forename: José
authors.initials: J
authors.lastname: Moreno-Barral
authors.forename: Felipe
authors.initials: F
authors.lastname: Moreno
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Castillo
mesh_terms: D001118:Argentina; D003105:Colombia; D005260:Female; D005808:Genes, Recessive; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D013030:Spain
chemical_list: D008565:Membrane Proteins; C118457:OTOF protein, human