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.

Nonsyndromic Hearing Loss Caused by a Mitochondrial T7511C Mutation

“…Genomic DNA was amplified by polymerase chain reaction (PCR) using primer pairs corresponding to nucleotide positions 7397 to 7417 and 7633 to 7617 in a thermal cycler (ABI model 9700; Applied Biosystems, Foster City, CA). 7 PCR conditions were as follows: initial denaturation at 94°C for 5 minutes, followed by 30 three-step cycles (94°C for 30 sec, 58°C for 30 sec, and 72°C for 1 min), with a final extension at 72°C for 5 minutes. After removing unincorporated dNTPs and primers, PCR products were directly sequenced in an ABI 310 Genetic Analyzer using the ABI Big Dye Terminator cycle sequencing reaction kit (Applied Biosystems) according to the manufacturer's instructions.…”

“…In Japan, no mutations in the tRNA Ser(UCN) gene have been found except for the A7445G mutation, which was detected in one family with maternally inherited palmoplantar keratoderma and progressive SNHL. 7 We describe a Japanese family showing nonsyndromic SNHL with a possible maternal inheritance pattern. We identified a T7511C mutation in maternally related family members.…”

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – Diagnostic algorithm and principles of therapy

“…7 Finally, a maternally inherited PPK with deafness due to a mutation in the mitochondrial MTTS1 gene has been described. 8 Mutilating palmoplantar keratoderma with deafness due to GJB2 mutations classic variant (Vohwinkel syndrome) VS, due to autosomal dominant GJB2 mutations, is characterized by congenital deafness, diffuse PPK with a honeycomb pattern (yellow hyperkeratosis with typical pits) and starfish keratoses on knuckles and wrists 4 (Fig. 1).…”

“…Palmoplantar keratoderma with deafness due to MTTS1 gene mutation This form of PPK with deafness is maternally inherited as it is caused by a mutation in the mitochondrial MTTS1 gene 16,17 (Table S1), encoding the mitochondrial tRNA for serine (UCN). 8,[18][19][20] PPKs may develop from childhood to adolescence and may be diffuse or focal, showing an honeycomb appearance. Postlingual hearing loss starts in childhood.…”

Mitochondrial dysfunction: a neglected component of skin diseases

“…In addition, the mutation exerts long-range effects, reducing the expression of the ND6 gene (encoding a subunit of complex I), which is co-transcribed with the eight tRNA genes of the mitochondrial light strand. On the heavy strand of the mtDNA, the mutation changes a stop codon of the MT-COI subunit of complex IV (cytochrome c oxidase) to a different stop codon(29)(30)(31)(32)(33)(158)(159)(160).…”