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Several connexin genes (GJB1, GJB2, GJB3, GJB6 and GJA1) have been found mutated in patients with non-syndromic and/or syndromic deafness indicating an important role of these proteins in the auditory system. In order to better understand the function of the connexins in the inner ear we have analyzed the gene expression profiles of two connexin genes, Gjb1 (connexin 32) and Gjb3 (connexin 31), by in situ hybridization during the mouse cochlea organogenesis, from early otocyst up to the mature organ in adult. In the developing otocyst epithelium, some restricted domains expressed Gjb3 and Gjb1 whilst high levels of both transcripts were present in the surrounding mesenchymal tissue. As development proceeds, expression of these two genes was found in various subtypes of fibrocytes, either within the spiral limbus or along the spiral ligament, as well as in the basilar membrane cells, in the Reissner's membrane cells, and in subsets of the cellular elements of the cochlear ganglion. Gjb3 and Gjb1 expression was spatiotemporally modulated within the sensory hair cells and the various supporting cells that compose the developing organ of Corti. A transitory expression of Gjb1 was found in the basal and intermediate cells of the stria vascularis. In the adult cochlea Gjb1 transcripts disappeared while Gjb3 expression remained present in fibrocytes with specific expression patterns.

Gap junctions are important structures in cell-to-cell communication. Connexins, the protein units of gap junctions, are involved in several human disorders. Mutations in beta-connexin genes cause hearing, dermatological and peripheral nerve disorders. Recessive mutations in the gene encoding connexin 26 (GJB2) are the most common cause of childhood-onset deafness. The combination of mutations in the GJB2 and GJB6 (Cx30) genes also cause childhood hearing impairment. Although both recessive and dominant connexin mutants are functionally impaired, dominant mutations might have in addition a dominant-negative effect on wild-type connexins. Some dominant mutations in beta-connexin genes have a pleiotropic effect at the level of the skin, the auditory system and the peripheral nerves. Understanding the genotype-phenotype correlations in diseases caused by mutations in connexin genes might provide important insight into the mechanisms that lead to these disorders.

Mutations in GJB1, GJB2, GJB3 and GJB6 are involved in hearing impairment. GJB2, GJB3 and GJB6 are also mutated in patients with hyperproliferative skin disorders. The human GJB4 gene has been deduced in silico and a mutation in a family with erythrokeratodermia variabilis has been reported. We describe here the analysis of the GJB4 gene in hearing impairment patients and control subjects. We have identified a common (4%) frameshift mutation (154del4) in GJB4 in both affected and hearing subjects, one patient being homozygous for the mutation. We have also detected five amino acid variants (R103C, R124Q, R160C, C169W and E204A) in individuals that have not skin disorders. While mutation 154del4 is not associated with hearing impairment the involvement of some of the amino acid variants detected here is uncertain. These GJB4 variants should help to define the putative role of connexin 30.3 in both skin disorders and hearing impairment., (Copyright 2002 Wiley-Liss, Inc.)

Several connexin genes (GJB1, GJB2, GJB3, GJB6 and GJA1) have been found mutated in patients with non-syndromic and/or syndromic deafness indicating an important role of these proteins in the auditory system. In order to better understand the function of the connexins in the inner ear we have analyzed the gene expression profiles of two connexin genes, Gjb1 (connexin 32) and Gjb3 (connexin 31), by in situ hybridization during the mouse cochlea organogenesis, from early otocyst up to the mature organ in adult. In the developing otocyst epithelium, some restricted domains expressed Gjb3 and Gjb1 whilst high levels of both transcripts were present in the surrounding mesenchymal tissue. As development proceeds, expression of these two genes was found in various subtypes of fibrocytes, either within the spiral limbus or along the spiral ligament, as well as in the basilar membrane cells, in the Reissner''s membrane cells, and in subsets of the cellular elements of the cochlear ganglion. Gjb3 and Gjb1 expression was spatiotemporally modulated within the sensory hair cells and the various supporting cells that compose the developing organ of Corti. A transitory expression of Gjb1 was found in the basal and intermediate cells of the stria vascularis. In the adult cochlea Gjb1 transcripts disappeared while Gjb3 expression remained present in fibrocytes with specific expression patterns. [Copyright &y& Elsevier]

Mutations in the GJB2 gene have been identified in many patients with childhood deafness, 35delG being the most common mutation in Caucasoid populations. We have analyzed a total of 576 families/unrelated patients with recessive or sporadic deafness from Italy and Spain, 193 of them being referred as autosomal recessive, and the other 383 as apparently sporadic cases (singletons). Of the 1152 unrelated GJB2 chromosomes analyzed from these patients, 37% had GJB2 mutations. Twenty-three different mutations were detected (1 in-frame deletion, 4 nonsense, 5 frameshift, and 13 missense mutations). Mutation 35delG was the most common, accounting for 82% of all GJB2 deafness alleles. The relative frequency of 35delG in Italy and Spain was different, representing 88% of the alleles in Italian patients and only 55% in the Spanish cases. Eight non-35delG mutations were detected more than once (V37I, E47X, 167delT, L90P, 312del14, 334delAA, R143W, and R184P), with relative frequencies ranging between 0.5 and 1.6% of the GJB2 deafness alleles. The information based on conservation of amino acid residues, coexistence with a second GJB2 mutation or absence of the mutation in non-deaf control subjects, suggests that most of these missense changes should be responsible for the deafness phenotype. [ABSTRACT FROM AUTHOR]