Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins

Abstract

Deafness is a complex disorder that involves a high number of genes and environmental factors. There has been enormous progress in non‐syndromic deafness research during the last five years, with the identification of over 50 loci and 15 genes. Among these, three genes, GJB2, GJB3, and GJB6, encode for connexin proteins (Connexin26, Connexin31, and Connexin30, respectively). Another connexin (Connexin32, encoded by GJB1) is involved in X‐linked peripheral neuropathy and hearing impairment. Mutations in these genes cause autosomal recessive (GJB2 and GJB3), autosomal dominant (GJB2, GJB3, and GJB6) or X‐linked (GJB1) hearing impairment, both syndromic (GJB2, keratoderma; GJB3 erythrokeratodermia variabilis; and GJB1, peripheral neuropathy), and non‐syndromic (GJB2, GJB3, and GJB6). Among these genes, mutations in GJB2 account for about 50% of all congenital cases of hearing impairment. Three mutations in GJB2 (35delG, 167delT, and 235delC) are particularly common in specific populations (Caucasoid, Jewish Ashkenazi, and Oriental, respectively), leading to carrier frequencies between one in 30 and one in 75. Over 50 mutations have been identified in the GJB2 gene, of which some missense changes (M34T, W44C, G59A, D66H, and R75W) have a negative dominant action in hearing impairment, with partial to full penetrance. Functional studies for some missense mutations in connexins 26, 30, and 32 have indicated abnormal gap junction conductivity. Expression patterns in mouse and rat cochlea indicate that Connexin26 and Connexin30 are expressed in the supportive cells of the cochlea, suggesting a potential role in endolymph potassium recycling. The high prevalence of mutations in GJB2 in some populations provides the tools for molecular diagnosis, carrier detection, and prenatal diagnosis of congenital hearing impairment. Hum Mutat 16:190–202, 2000. © 2000 Wiley‐Liss, Inc.

Oculodentodigital Dysplasia-causing Connexin43 Mutants Are Non-functional and Exhibit Dominant Effects on Wild-type Connexin43

“…Furthermore, both mutants have a dominantnegative effect on wild-type Cx43 channels as assessed by impairment of dye transfer. These findings are consistent with what is known about disease-causing mutations in other connexin genes (38) and extend earlier speculations as to how mutations in Cx43 may affect function (18).…”

Connexin and pannexin hemichannels of neurons and astrocytes

“…Mutations in Cx30 are associated with deafness. 53 In HeLa cells, expressed Cx30 gap junctions had properties expected of members of this family of proteins. There were two conductance states (179 and 48 pS) and a strong dependence upon junctional voltage with a half voltage of inactivation of ±27 mV 7 (Table 1).…”

Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene

“…2 This gene has also been implicated in an autosomal dominant form of NSSNHL and in syndromic deafness. 3,4 More than 60 different GJB2 amino-acid substitutions have been reported to date as recessive (DFNB1) and dominant (DFNA3) (MIM 6011544) hearing loss alleles (see The Connexin-Deafness Homepage). One of these, M34T is a missense mutation affecting a methionine in the first transmembrane domain of GJB2, conserved in GJB1 and GJB2 but not in other b-connexins.…”