title: Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans.
abstract: Non-syndromic neurosensory autosomal recessive deafness (NSRD) is the most common form of genetic hearing loss. Previous studies defined at least 15 human NSRD loci. Recently we demonstrated that DFNB1, located on the long arm of chromosome 13, accounts for approximately 80% of cases in the Mediterranean area. Further analysis with additional markers now identifies several recombinants which narrow the candidate region to approximately 5 cM, encompassed by markers D13S141 and D13S232 and including several ESTs and candidate genes, including the connexin26 (GJB2) gene. Analysis of PCR products from our affected patients' DNA shows two frameshift mutations in the connexin26 gene. Deletion of a G within a stretch of six Gs at position 35 of the GJB2 cDNA (mutation 35delG) leads to premature chain termination and is present in 63% of NSRD chromosomes, demonstrating linkage to chromosome 13. Deletion of a T at position 167 of GJB2 (mutation 167delT), also resulting in premature chain termination, was detected in another patient. Four neutral sequence polymorphisms were also identified. These findings are in agreement with a recent study showing that mutations in the connexin26 gene are associated with genetic forms of deafness in three Pakistani families and that GJB2 is DFNB1. Connexin26 is a member of a large family of proteins involved in formation of gap junctions, which are involved in electrical synapses and the direct transfer of small molecules and ionic currents between neighboring cells. The identification of GJB2 as the DFNB1 gene should provide a better understanding of the biology of normal and abnormal hearing, help form the basis for diagnosis and may facilitate development of strategies for treatment of this common genetic disorder.
authors.affiliation: Servizio di Genetica Medica, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Zelante
authors.forename: P
authors.initials: P
authors.lastname: Gasparini
authors.forename: X
authors.initials: X
authors.lastname: Estivill
authors.forename: S
authors.initials: S
authors.lastname: Melchionda
authors.forename: L
authors.initials: L
authors.lastname: D'Agruma
authors.forename: N
authors.initials: N
authors.lastname: Govea
authors.forename: M
authors.initials: M
authors.lastname: Milá
authors.forename: M D
authors.initials: MD
authors.lastname: Monica
authors.forename: J
authors.initials: J
authors.lastname: Lutfi
authors.forename: M
authors.initials: M
authors.lastname: Shohat
authors.forename: E
authors.initials: E
authors.lastname: Mansfield
authors.forename: K
authors.initials: K
authors.lastname: Delgrosso
authors.forename: E
authors.initials: E
authors.lastname: Rappaport
authors.forename: S
authors.initials: S
authors.lastname: Surrey
authors.forename: P
authors.initials: P
authors.lastname: Fortina
mesh_terms: D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D017931:DNA Primers; D003638:Deafness / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics*; D006314:Hearing Loss, Conductive / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D019083:Mediterranean Region; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA
chemical_list: D017630:Connexins; D017931:DNA Primers; C000607042:GJB2 protein, human; D005819:Genetic Markers; D000072259:Connexin 26