A Novel Mutation Identified in the <i>DFNA5</i> Gene in a Dutch Family: A Clinical and Genetic Evaluation

Abstract

A novel DFNA5 mutation was found in a Dutch family, of which 37 members were examined. A nucleotide substitution was identified in the splice acceptor site of intron 7, leading to skipping of exon 8 in part of the transcripts. The mutation was found in 18 individuals. Sensorineural hearing impairment was non-syndromic and symmetric. In early life, presumably congenitally, hearing impairment amounted to 30 dB in the high frequencies. Progression was most pronounced at 1 kHz (1.8 dB/year). Speech recognition was relatively good with a phoneme score of about 50% at the age of 70. Onset age was 37 years, and recognition deteriorated by 1.3% per year. The recognition score deteriorated by 1.0% per decibel threshold increase from a mean pure-tone average (PTA at 1, 2 and 4 kHz) of 63 dB onwards. Vestibular function was generally normal. The second mutation identified in the DFNA5 gene results in hearing impairment, similar to that in the original DFNA5 family in terms of pure-tone thresholds, but with more favourable speech recognition.

A novel DFNA5 mutation does not cause hearing loss in an Iranian family

“…This mutation is only the fourth in DFNA5 to be described. The first three mutations, although different at the genomic level, share the common feature of causing exon 8 skipping (Bischoff et al 2004;Van Laer et al 1998;Yu et al 2003). The resulting aberrant mRNA escapes degradation by nonsense-mediated mRNA decay as most of the protein is left intact.…”

“…Unfortunately, Dfna5-/-mice did not represent a good model for DFNA5-associated hearing loss as hearing loss did not develop, even at older ages (Van Laer et al 2005). Interestingly, 5 years after the description of the original DFNA5 mutation, two additional DFNA5 mutations were reported: a deletion of three nucleotides in the polypyrimidine tract of intron 7 in a Chinese family (Yu et al 2003), and a nucleotide substitution in the splice-acceptor site of intron 7 in a Dutch family (Bischoff et al 2004). The hearing loss in all three DFNA5 families is very similar and, although these mutations differ at the genomic DNA level, they all lead to exon 8 skipping at the mRNA level.…”

The potential role of DFNA5, a hearing impairment gene, in p53-mediated cellular response to DNA damage

“…Thus far, two additional mutations in DFNA5 have been reported in a Chinese family and another Dutch family. Interestingly, these mutations also cause skipping of exon 8, thereby resulting in the generation of the same aberrant transcript as in the case of the first Dutch family identified with the mutations (Yu et al 2003;Bischoff et al 2004). Therefore, it was speculated that hearing impairment may not be due to haploinsufficiency but rather due to a gain-of-function mutation.…”

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

“…2 These families all have different genomic DFNA5 mutations, but in each case the DFNA5 mRNA transcript skips exon 8, resulting in a frameshift and a premature truncation of the protein. [1][2][3][4][5] These findings have led to the hypothesis that DFNA5-associated HL is attributable to a highly specific gain-of-function mutation, in which skipping of one exon causes disease while mutations in other parts of this gene may not result in HL at all. Further experimental evidence for this hypothesis was provided by the finding that transfection of mutant DFNA5 causes cell death in both yeast 6 and mammalian 7 cells and by the discovery of a new DFNA5 mutation.…”