title: M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance.
abstract: Despite research the role of the M34T and V37I variants of GJB2 in causing hearing impairment (HI) remains controversial. Our purpose was to test a hypothesis that M34T and V37I are pathogenic but have distinct features resulting in a reduced penetrance. We screened for known GJB2/GJB6 mutations 233 Polish consecutive unrelated subjects with non-syndromic, sensorineural HI who were previously found to carry 35delG mutation on one chromosome. The most frequent mutations were also analyzed in approximately 1,000 controls. We found that M34T and V37I were significantly (P << 10(-6)) overrepresented among patients, but their penetrance was estimated as 1/10 relative to mutations of undisputed pathogenicity. This finding apparently could not be explained by low degree of HI associated with M34T and V37I since another mutation causing comparably mild HI (L90P) did not have reduced penetrance. Subsequent analyses showed that the patients with M34T/35delG and V37I/35delG had significantly later onset of HI than patients with other genotypes (P < 10(-6)) including the L90P/35delG (P = 0.006). Also, among these patients (but not others) a strong correlation between the degree of HI and its duration was found (r = 0.79, P < 10(-5)). We tentatively suggest that M34T and V37I might cause mild HI characterized by relatively late onset and progression.
authors.affiliation: Institute of Physiology and Pathology of Hearing, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Pollak
authors.forename: Agata
authors.initials: A
authors.lastname: Skórka
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Mueller-Malesińska
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kostrzewa
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Kisiel
authors.forename: Jarosław
authors.initials: J
authors.lastname: Waligóra
authors.forename: Paweł
authors.initials: P
authors.lastname: Krajewski
authors.forename: Monika
authors.initials: M
authors.lastname: Ołdak
authors.forename: Lech
authors.initials: L
authors.lastname: Korniszewski
authors.forename: Henryk
authors.initials: H
authors.lastname: Skarzyński
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
mesh_terms: D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D015331:Cohort Studies; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D004247:DNA / Q000032:analysis / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D019683:Penetrance; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26; D004247:DNA