Deafness, Autosomal Dominant 51

A number sign (#) is used with this entry because autosomal dominant deafness-51 (DFNA51) is caused by a 269-kb duplication of chromosome 9q21.11 involving the TJP2 (607709) and FAM189A2 (607710) genes.

Clinical Features

Walsh et al. (2010) reported a large 4-generation Jewish family of Tunisian descent with age-related progressive sensorineural hearing loss. Pure tone audiometry showed hearing loss with onset in the fourth decade, first affecting high frequencies and later becoming severe to profound at all frequencies. There was no evidence of vertigo, dizziness, disequilibrium, or imbalance.

Inheritance

In the family with DFNA51 reported by Walsh et al. (2010), the transmission pattern was consistent with autosomal dominant inheritance.

Mapping

By genomewide linkage analysis of a large Jewish family with age-related hearing loss, Walsh et al. (2010) identified a locus, which they designated DFNA51, on chromosome 9p13.3-q21.13 (maximum Z score of 6.56 at D9S175).

Molecular Genetics

In affected members of a large Jewish family with DFNA51, Walsh et al. (2010) identified a tandem inverted duplication of the pericentromeric region of chromosome 9 spanning positions 71,705,804 to 71,974,823 for a size of approximately 269 kb. The duplication included the entire locus for the TJP2 gene, which spans positions 71,788,971 to 71,870,124. The distal breakpoint occurred in intron 2 of the FAM189A2 gene; however, there was no evidence of a mutant FAM189A2 transcript, and no correlation of genotype with expression of full-length FAM189A2 in the family, leading the authors to focus their studies on the duplication of TJP2. No mutations in the TJP2 gene were found; the sequence of the gene in affected individuals was wildtype. Studies of mouse tissues showed that Tjp2 is developmentally regulated in the inner ear. Studies of DFNA51 patient lymphoblasts showed that endogenous levels of TJP2 were increased approximately 2-fold, consistent with overexpression of the gene resulting from the inverted duplication. This overexpression was associated with decreased amounts of phosphorylated GSK3B (605004), indicating increased GSK3B activity, which makes cells more susceptible to apoptosis. Specific analysis of apoptosis-related genes in patient lymphoblasts showed a shift in expression of BCL2 (151430) family genes, such as BID (601997), BCL2L1 (600039), and TSPO (109610), that would favor apoptosis. Walsh et al. (2010) hypothesized that TJP2 overexpression increases the susceptibility of inner ear cells to apoptosis, leading to progressive hearing loss.