Autosomal Dominant Hearing Impairment Research Articles

Correction: Mutations in the gene encoding gap junction protein β–3 associated with autosomal dominant hearing impairment

Correction: Mutations in the gene encoding gap junction protein β–3 associated with autosomal dominant hearing impairment

The DFNA2 locus for hearing impairment: two genes regulating K+ ion recycling in the inner ear.

DFNA2 is a locus for autosomal dominant non-syndromal hearing impairment (ADNSHI) located on chromosome 1p34 and six linked families have been identified. An audiometric study of these families showed that despite small differences in the phenotype all families suffer from progressive hearing impairment starting in the high frequencies. A detailed genetic analysis revealed that this deafness locus contains more than one gene responsible for hearing impairment. Thus far, two genes on chromosome 1p34 have been implicated in ADNSHI. The first, connexin 31 (GJB3), is a member of the connexin gene family. Connexins form gap junctions. These are connections between neighbouring cells that allow transport of small molecules. GJB3 mutations were found in two small Chinese families with ADNSHI. The second is KCNQ4, a voltage-gated K+ channel. Mutations in KCNQ4 were first found in a small French family, later in five of the six linked DFNA2 families. No GJB3 or KCNQ4 mutations were detected in patients of an extended Indonesian DFNA2 family. Two pathways have been proposed for the recycling of K+ from the hair cells back to the endolymph. These pathways involve the use of gap junctions, K+ pumps and K+ channels. The expression of GJB3 and KCNQ4 in the inner ear and their functions suggest that both DFNA2 genes may play a role in K+ homeostasis.

Non-syndromal autosomal dominant hearing impairment: ongoing phenotypical characterization of genotypes.

This review is concerned with the present state of phenotypical characterization of known genotypes of non-syndromal autosomal dominant hearing impairment. A brief outline of history and context of phenotyping and genotyping of hearing impairment is given with particular reference to the most recent developments in this field, followed by descriptions of DFNA1, DFNA2, DFNA5, DFNA6/14, DFNA8/12, DFNA9, DFNA 13, DFNA17 and DFNA21. Phenotyping those known genotypes may support the ongoing search for mutations in the corresponding gene and enhance genetic counselling. It is recommended that sufficient attention is given to a detailed description of the phenotype in each (newly) described hereditary hearing impairment disorder.

Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.

Hearing impairment is the most commonly occurring condition that affects the ability of humans to communicate. More than 50% of the cases of profound early-onset deafness are caused by genetic factors. Over 40 loci for non-syndromic deafness have been genetically mapped, and mutations in several genes have been shown to cause hearing loss. Mutations in the gene encoding connexin 26 (GJB2) cause both autosomal recessive and dominant forms of hearing impairment. To study the possible involvement of other members of the connexin family in hereditary hearing impairment, we cloned the gene (GJB3) encoding human gap junction protein beta-3 using homologous EST searching and nested PCR. GJB3 was mapped to human chromosome 1p33-p35. Mutation analysis revealed that a missense mutation and a nonsense mutation of GJB3 were associated with high-frequency hearing loss in two families. Moreover, expression of Gjb3 was identified in rat inner ear tissue by RT-PCR. These findings suggest that mutations in GJB3 may be responsible for bilateral high-frequency hearing impairment.

Nonsyndromic hearing impairment is associated with a mutation in DFNA5.

Nonsyndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 loci mapped on the human genome, however, only a limited number of genes implicated in hearing loss have been identified. We previously reported linkage to chromosome 7p15 for autosomal dominant hearing impairment segregating in an extended Dutch family (DFNA5). Here, we report a further refinement of the DFNA5 candidate region and the isolation of a gene from this region that is expressed in the cochlea. In intron 7 of this gene, we identified an insertion/deletion mutation that does not affect intron-exon boundaries, but deletes five G-triplets at the 3' end of the intron. The mutation co-segregated with deafness in the family and causes skipping of exon 8, resulting in premature termination of the open reading frame. As no physiological function could be assigned, the gene was designated DFNA5.