| #601544 | ||||||||||||||||||||||||
| DEAFNESS, AUTOSOMAL DOMINANT 3A; DFNA3A | ||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||
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| Phenotypic Series | ||||||||||||||||||||||||
| Clinical Synopsis | ||||||||||||||||||||||||
| TEXT | ||||||||||||||||||||||||
| A number sign (#) is used with this entry because DFNA3A can be caused by mutation in the connexin-26 gene (GJB2; 121011) on chromosome 13q11-q12. See also DFNA3B (612643), which is caused by mutation in the connexin-30 gene (GJB6; 604418) on chromosome 13q12. | ||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||
| By linkage analysis, Chaib et al. (1994) mapped a dominant form of sensorineural nonsyndromic deafness to chromosome 13q11. | ||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||
| Kelsell et al. (1997) identified a mutation in the GJB2 gene (M34T; 121011.0001) in affected members of a pedigree segregating autosomal dominant deafness. They also identified mutations in the GJB2 gene in 3 autosomal recessive nonsyndromic sensorineural deafness pedigrees (DFNB1A; 220290). Kelley et al. (1998) presented evidence that the M34T missense mutation found by Kelsell et al. (1997) was not sufficient to cause hearing loss. They found this allele in a recessive deafness family where it was segregating independently of the hearing loss phenotype; they also found the allele in 3 of 192 control chromosomes, suggesting that it may be a common polymorphism. In 4 individuals over 3 generations of a Turkish family with autosomal dominant nonsyndromic congenital profound hearing loss, Piazza et al. (2005) identified heterozygosity for a missense mutation in the GJB2 gene (R75Q; 121011.0026). Cell transfection and fluorescence imaging, dye transfer experiments, and dual patch clamp recording showed that the mutant protein completely prevented the formation of functional channels. In all affected members of a large French family with late childhood onset of autosomal dominant isolated hearing loss, Morle et al. (2000) identified a heterozygous mutation in the GJB2 gene (121011.0018). The hearing loss was detected between 10 and 20 years of age. There was significant intrafamilial variability for the severity of the hearing loss, which was restricted to high frequencies during the first decade and progressed to middle frequencies between 10 and 50 years of age. In affected members of a family with early-onset severe to profound nonsyndromic hearing loss, Tekin et al. (2001) identified a heterozygous mutation in the GJB2 gene (W44C; 121011.0019). The mutation had previously been described in association with prelingual nonsyndromic deafness in 2 families originating from the same geographic region of France (Denoyelle et al., 1998). Iossa et al. (2010) reported an Italian family in which an unaffected mother and 1 of her deaf sons were both heterozygous for an allele carrying 2 GJB2 mutations in cis: the dominant R75Q (121011.0026) and the recessive 35delG (121011.0005), whereas her other deaf son did not carry either of these mutations. The results suggested that the recessive mutation 'canceled out' the effect of the dominant mutation by causing a truncated protein before reaching residue 75. Iossa et al. (2010) suggested that the deafness in the 2 sons was due to another genetic cause and highlighted the importance of the report for genetic counseling. | ||||||||||||||||||||||||
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