Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene

Abstract

We studied a large Dutch family with maternally inherited, progressive, sensorineural hearing loss in 27 patients. Only in a single family member was the hearing loss accompanied by neurological symptoms including ataxia and dysarthria. DNA analysis of the mitochondrial genome revealed the insertion of a C at nucleotide position 7472 in the tRNA Ser(UCN) gene (7472insC mutation). We determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leucocyte heteroplasmy. The 7472insC mutation was previously identified in a smaller family from Sicily with sensorineural hearing loss in 9 family members, six of them also presenting neurologically with ataxia and myoclonus. The presence of the 7472insC mutation in two different pedigrees strongly supports its pathogenicity. However, the interfamilial difference in penetrance of the neurologic abnormalities is most likely to be strongly influenced by secondary factors different from the 7472insC mutation, as heteroplasmy or age of the patients were similar in both families. This mutation should therefore be analysed in families with maternally inherited hearing loss, irrespective of whether the hearing loss is non-syndromic or accompanied by neurologic abnormalities.

Cosegregation of the G7444A mutation in the mitochondrial COI/tRNASer(UCN) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside‐induced and nonsyndromic hearing loss

“…Of these, four non-syndromic deafness-associated mutations: A7445G [Reid et al, 1994;Fischel-Ghodsian et al, 1995], 7472insC [Verhoeven et al, 1999;Jacobs et al, 2005], T7510C [Hutchin et al, 2000;del Castillo et al, 2002] and T7511C [Sue et al, 1999;Li et al, 2005a], have been identified in the tRNA Ser(UCN) gene. The C1494T mutation in the highly conserved decoding site of the 12S rRNA has been associated with both aminoglycoside-induced and nonsyndromic hearing loss in a large Chinese family [Zhao et al, 2004a;Zhao et al, 2005].…”

Maternally inherited hearing impairment in a family with the mitochondrial DNA A7445G mutation

“…Several mtDNA point mutations have been reported in families with maternally inherited NSSHI; the A1555G mutation in the 12S rRNA gene, which also causes hypersensitivity to aminoglycosides 1,2 and four mutations affecting the tRNASer (UCN) gene -A7445G, 7472insC, T7510C and T7511C. [3][4][5][6][7] The frequency of these mutations in the general population has yet to be determined. Both the A1555G and A7445G mutations have been reported in different ethnic populations raising the possibility that such mutations are more common causes of hearing loss than initially thought.…”

Mitochondrial rRNA and tRNA and hearing function

“…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. The mutation is heteroplasmic, although most individuals have over 90% of abnormal mitochondrial chromosomes in the tissues examined [46]. The 7472insC mutation seems to occur multiple times in the European population than others.…”

“…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.…”