A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy.
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.
Rodríguez-Ballesteros
Montserrat
M
Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain.
Reynoso
Raúl
R
Olarte
Margarita
M
Villamar
Manuela
M
Morera
Constantino
C
Santarelli
Rosamaria
R
Arslan
Edoardo
E
Medá
Carme
C
Curet
Carlos
C
Völter
Christiane
C
Sainz-Quevedo
Manuel
M
Castorina
Pierangela
P
Ambrosetti
Umberto
U
Berrettini
Stefano
S
Frei
Klemens
K
Tedín
Socorro
S
Smith
Janine
J
Cruz Tapia
M
M
Cavallé
Laura
L
Gelvez
Nancy
N
Primignani
Paola
P
Gómez-Rosas
Elena
E
Martín
Mirta
M
Moreno-Pelayo
Miguel A
MA
Tamayo
Martalucía
M
Moreno-Barral
José
J
Moreno
Felipe
F
del Castillo
Ignacio
I
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
D008565:Membrane Proteins; C118457:OTOF protein, human