Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment

Abstract

Mitochondrial mutations have previously been reported anecdotally in families with maternally inherited, nonsyndromic hearing impairment. To ascertain the contribution of mitochondrial mutations to postlingual but early-onset, nonsyndromic hearing impairment, we screened patients collected from within two different populations (southern Italy and UK) for previously reported mtDNA mutations associated with hearing disorders. Primer extension (SNP analysis) was used to screen for specific mutations, revealing cases of heteroplasmy and its extent. The most frequently implicated tRNA genes, Leu(UUR) and Ser(UCN), were also sequenced in all Italian patients. All tRNA genes were sequenced in those UK patients showing the clearest likelihood of maternal inheritance. Causative mtDNA mutations were found in approximately 5% of patients in both populations, representing almost 10% of cases that were clearly familial. Age of onset, where known, was generally before adulthood, and hearing loss was typically progressive. Haplogroup analysis revealed a possible excess of haplogroup cluster HV in the patients, compared with population controls, but of borderline statistical significance. In contrast, we did not find any of the previously reported mtDNA mutations, nor a significant deviation from haplogroup cluster frequencies typical of the control population, in patients with late adult-onset hearing loss (age-related hearing impairment) from the UK or Finland.

Non-syndromic Hearing Impairment in a Hungarian Family with the m.7510T>C Mutation of Mitochondrial tRNASer(UCN) and Review of Published Cases

“…The m.7510T>C mtDNA mutation was not detected in normal Caucasian controls (Hutchin et al 2000), nor in haplogroup-or sub-haplogroupmatched controls (Labay et al 2008). Although it was not found in some large screening populations with nonsyndromic SNHL (Jacobs et al 2005;Lévêque et al 2007), several families have already been described.…”

Mitochondrial rRNA and tRNA and hearing function

“…Most individuals carrying this mutation had progressive SNHL, and some of them were accompanied by a widespread neurological disease including ataxia, dysarthria, and myoclonic seizures. This mutation was later found in a large Dutch family [46] and in several sporadic subjects with nonsyndromic hearing loss [47]. In the Dutch family, the hearing loss is sensorineural progressive with onset in early adulthood, and only a single family member with hearing loss showed accompanying neurological symptoms.…”

“…In the mitochondrial tRNA Ser(UCN) gene, five nonsyndromic deafness-associated mutations, A7445G [42][43][44], 7472insC [45][46][47], T7510C [48,84], T7511C [49][50][51][52][53], and G7444A [55][56][57], have been found in families from various ethnic backgrounds. These mutations often occur in homoplasmy or in high levels of heteroplasmy, indicating a high threshold for pathogenicity.…”

“…Mutations in mitochondrial DNA (mtDNA) can cause both syndromic and nonsyndromic hearing loss [5,[7][8][9][10][11]. Causative mtDNA mutations were found in approximately 5% of patients in both southern Italy and UK populations with postlingual but early-onset nonsyndromic hearing impairment [12]. In another recent report by Hsu et al [9], deleterious mtDNA point mutations and/or abnormal mtDNA content or multiple deletions were identified in 20 of 31 subjects with definite mitochondrial syndromic hearing loss, and most of the molecular defects responsible for mitochondrial disorder associated with hearing impairment were mutations in tRNA and rRNA genes.…”

A novel method of detecting mitochondrial m.1494C>T and m.1555A>G mutations in a single PCR reaction using base-quenched probe

“…It has been demonstrated that mutation m.1494C>T might associate with aminoglycoside-induced hearing loss in a large Chinese family [8,10,11]., while the mutation m.1555A>G may contribute to both aminoglycoside-induced and nonsyndromic hearing loss in families worldwide [12,13]. Both m.1555A>G and m.1494C>T mutations locate in a highly conserved region of 12SrRNA that is implicated in aminoglycoside binding in bacteria.…”