Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness

Abstract

A New Zealand and a Scottish pedigree with maternally inherited sensorineural deafness were both previously shown to carry a heteroplasmic A7445G mutation in the mitochondrial genome. More detailed clinical examination of the New Zealand family showed that the hearing loss was progressive, with the severity of the overall loss and the frequencies most affected differing markedly between individuals of similar age, and showed that many relatives also had palmoplantar keratoderma. Review of the literature demonstrated three other large families with presumed autosomal dominant inheritance of palmoplantar keratoderma and hearing loss. In a United Kingdom pedigree the syndrome was transmitted by female and male parents, an inheritance pattern which made mitochondrial inheritance unlikely; however, in a Turkish and a Japanese pedigree the affected individuals were all maternally related. Subsequent analysis of the Japanese pedigree documented the same A7445G mitochondrial mutation as was previously found in the New Zealand and Scottish pedigrees. Other mitochondrial sequence variants previously reported in the New Zealand or Scottish pedigrees were absent from the Japanese pedigree which suggests that the A7445G mutation arose independently in all three pedigrees. To our knowledge palmoplantar keratoderma has not previously been associated with mitochondrial defects; however, the current findings suggest that the A7445G mutation is associated not only with progressive hearing loss but also with palmoplantar keratoderma. The penetrance and expressivity of both symptoms varied considerably between individuals in the Scottish and New Zealand Studies which suggests that additional environmental and/or genetic factors are involved.

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

“…3,7,8 mtDNA haplotype analysis of the three previous families with the A7445G mutation had shown they were unrelated. Similar analysis showed the family described here lacked the T4216C and G13708A base changes found in the New Zealand family 8 and the G14368C polymorphism of the Scottish family.…”

“…3,7,8 mtDNA haplotype analysis of the three previous families with the A7445G mutation had shown they were unrelated. Similar analysis showed the family described here lacked the T4216C and G13708A base changes found in the New Zealand family 8 and the G14368C polymorphism of the Scottish family. 9 No further sequence data was available on the Japanese family but since it is unlikely they are related to this family from Eastern Europe, the A7445G mutation has The presence of the A7445G mutation in four independent families provides further support that the mutation is pathogenic by itself though the reason for variation in penetrance between the families with the mutation is not known.…”

Mitochondrial rRNA and tRNA and hearing function

“…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.…”

“…The A7445G mutation was first described in a family from Scotland [42], and established in two unrelated pedigrees from New Zealand [43] and Japan [44]. In the latter two pedigrees, a mild form of the skin condition palmoplantar keratoderma also segregates in the matrilineal line, and the penetrance of this mutation for hearing loss is much higher than in the Scottish pedigree.…”

The 12S rRNA A1555G mutation in the mitochondrial haplogroup D5a is responsible for maternally inherited hypertension and hearing loss in two Chinese pedigrees

“…1,2 Those nonsyndromic deafness-associated mtDNA mutations, such as 12S rRNA A1555G or tRNA Ser(UCN) A7445G, often occur in the homoplasmy or nearly homoplasmy, [3][4][5][6] while the syndromic deafness-associated mtDNA mutations, such as the tRNA Leu(UUR) A3243G mutation and mtDNA large deletions, are present in heteroplasmy. 7,8 Furthermore, the A7445G mutation has also been associated with syndromic deafness presenting palmoplantar keratoderma, 9 while the A1555G mutation has been associated with Leber's hereditary optical neuropathy or with cardiomyopathy or pigmentary disturbances and spinal anomalies. [10][11][12] The other non-syndromic deafness-associated mtDNA mutations are the 12S rRNA C1494T mutation, the 7472insC, T7505C and T7511C mutations in the tRNA Ser(UCN) gene ,and the T12201C mutation in the tRNA His gene.…”