title: GJB2 mutations in Mongolia: complex alleles, low frequency, and reduced fitness of the deaf.
abstract: We screened the GJB2 gene for mutations in 534 (108 multiplex and 426 simplex) probands with non-syndromic sensorineural deafness, who were ascertained through the only residential school for the deaf in Mongolia, and in 217 hearing controls. Twenty different alleles, including four novel changes, were identified. Biallelic GJB2 mutations were found in 4.5% of the deaf probands (8.3% in multiplex, 3.5% in simplex). The most common mutations were c.IVS1 + 1G > A (c.-3201G > A) and c.235delC with allele frequencies of 3.5% and 1.5%, respectively. The c.IVS1 + 1G > A mutation appears to have diverse origins based on associated multiple haplotypes. The p.V27I and p.E114G variants were frequently detected in both deaf probands and hearing controls. The p.E114G variant was always in cis with the p.V27I variant. Although in vitro experiments using Xenopus oocytes have suggested that p.[V27I;E114G] disturbs the gap junction function of Cx26, the equal distribution of this complex allele in both deaf probands and hearing controls makes it a less likely cause of profound congenital deafness. We found a lower frequency of assortative mating (37.5%) and decreased genetic fitness (62%) of the deaf in Mongolia as compared to the western populations, which provides an explanation for lower frequency of GJB2 deafness in Mongolia.
authors.affiliation: The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Leonard M. Miller School of Medicine, Miami, Florida 33136, USA. mtekin@med.miami.edu
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.forename: Xia-Juan
authors.initials: XJ
authors.lastname: Xia
authors.forename: Radnaabazar
authors.initials: R
authors.lastname: Erdenetungalag
authors.forename: Filiz Basak
authors.initials: FB
authors.lastname: Cengiz
authors.forename: Thomas W
authors.initials: TW
authors.lastname: White
authors.forename: Janchiv
authors.initials: J
authors.lastname: Radnaabazar
authors.forename: Begzsuren
authors.initials: B
authors.lastname: Dangaasuren
authors.forename: Hakki
authors.initials: H
authors.lastname: Tastan
authors.forename: Walter E
authors.initials: WE
authors.lastname: Nance
authors.forename: Arti
authors.initials: A
authors.lastname: Pandya
mesh_terms: D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D003638:Deafness / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056084:Genetic Fitness; D006801:Humans; D008297:Male; D008986:Mongolia
chemical_list: D017630:Connexins; C000607045:GJB2 protein, Xenopus; C000607042:GJB2 protein, human; D000072259:Connexin 26