A novel point mutation in the mitochondrial tRNA(Ser(UCN)) gene detected in a family with MERRF/MELAS overlap syndrome.

We found a new point mutation in the mitochondrial tRNA(Ser(UCN)) gene in a family with MERRF/MELAS overlap syndrome by screening for heteroplasmy by means of chemical cleavage of mismatch (CCM). Our strategy was based on the previous observations that most pathogenic mtDNA mutations in mitochondrial encephalomyopathies are heteroplasmic, whereas almost all neutral mitochondrial polymorphisms are homoplasmic. CCM followed by nucleotide sequencing of the corresponding region of the mitochondrial genome revealed a heteroplasmic mutation at nt 7512 in the tRNA(Ser(UCN)) gene. The 7512 (T to C) mutation disrupts a highly conserved base pair in the acceptor stem, and this mutation was not found in any of 120 normal controls, or in 43 patients with mitochondrial diseases. The proportion of the mutant mtDNA was 93% in muscle, 76 and 87% in the blood of the patients. A family member without apparent neuromuscular symptoms carried less mutant mtDNA. These findings support the view that this mutation is pathogenic in this family. Detection of heteroplasmy by CCM is an efficient means of screening pathogenic mtDNA point mutations.