title: A novel splice-site mutation in the GJB2 gene causing mild postlingual hearing impairment.
abstract: The DFNB1 subtype of autosomal recessive, nonsyndromic hearing impairment, caused by mutations affecting the GJB2 (connexin-26) [corrected] gene, is highly prevalent in most populations worldwide. DFNB1 hearing impairment is mostly severe or profound and usually appears before the acquisition of speech (prelingual onset), though a small number of hypomorphic missense mutations result in mild or moderate deafness of postlingual onset. We identified a novel GJB2 splice-site mutation, c. -22-2A>C, in three siblings with mild postlingual hearing impairment that were compound heterozygous for c. -22-2A>C and c.35delG. Reverse transcriptase-PCR experiments performed on total RNA extracted from saliva samples from one of these siblings confirmed that c. -22-2A>C abolished the acceptor splice site of the single GJB2 intron, resulting in the absence of normally processed transcripts from this allele. However, we did isolate transcripts from the c. -22-2A>C allele that keep an intact GJB2 coding region and that were generated by use of an alternative acceptor splice site previously unknown. The residual expression of wild-type connexin-26 [corrected] encoded by these transcripts probably underlies the mild severity and late onset of the hearing impairment of these subjects.
authors.affiliation: Unidad de Genética Molecular, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gandía
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Del Castillo
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Rodríguez-Álvarez
authors.forename: Gema
authors.initials: G
authors.lastname: Garrido
authors.forename: Manuela
authors.initials: M
authors.lastname: Villamar
authors.forename: Manuela
authors.initials: M
authors.lastname: Calderón
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Moreno-Pelayo
authors.forename: Felipe
authors.initials: F
authors.lastname: Moreno
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Castillo
mesh_terms: D001483:Base Sequence; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D005260:Female; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D020033:Protein Isoforms; D000072259:Connexin 26
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