A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies

Abstract

Mitochondrial encephalomyopathies are usually divided into three distinct clinical subgroups: (1) mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); (2) myoclonus epilepsy associated with ragged-red fibres (MERRF); and (3) chronic progressive external ophthalmoplegia (CPEO) including Kearns-Sayre syndrome. Large deletions of human mitochondrial DNA and a transition mutation at the mitochondrial transfer RNALys gene give rise to CPEO including Kearns-Sayre syndrome and MERRF, respectively. Here we report an A-to-G transition mutation at nucleotide pair 3,243 in the dihydrouridine loop of mitochondrial tRNA(Leu)(UUR) that is specific to patients with MELAS. Because this mutation creates an ApaI restriction site, we could perform a simple molecular diagnostic test for the disease. The mutation was present in 26 out of 31 independent MELAS patients and 1 out of 29 CPEO patients, but absent in the 5 MERRF and 50 controls tested. Southern blot analysis confirmed that the mutant DNA always coexists with the wild-type DNA (heteroplasmy).

Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

“…[9][10][11][12] In contrast, the m.3243A4G mutation causes several major clinical phenotypes of mitochondrial disease such as myopathy, encephalopathy, lactic acidosis, stroke-like episodes, maternally inherited diabetes and deafness, chronic progressive external ophthalmoplegia and mitochondrial diabetes. [31][32][33] However, epidemiological evidence of the prevalence of the patients with the m.3243A4G mutation in the population still has limitations. The patients with m.3243A4G including asymptomatic cases in the general population are thought to be as common as 6.57-16.3 per 100 000.…”

Quantitation of a mitochondrial DNA deletion in Parkinson's disease

“…It is possible that small deletions and/or mutations undetectable on Southern blots may be present and accumulate in mtDNA of Parkinson patients, as is the case in other neurological diseases (mitochondrial encephalomyopathies [21,22] and Lebers hereditary optic neuropathy [23]). Sequence analysis of mtDNA should confirm or exclude the involvement of mitochondrial …”

Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

“…[5][6][7][8][9] The clinical hallmark of MELAS is stroke-like episodes that cause the abrupt onset of focal neurological deficits at a young age. Neuroimaging studies and measurement of blood lactate are useful screening tests for the diagnosis of MELAS, though the definite diagnosis of MELAS relies on the ragged red fibers (RRFs) or strongly succinate dehydrogenase-stained vessels (SSVs) demonstrated by muscle biopsy, or the causative mtDNA mutation confirmed by molecular genetic studies.…”

“…Neuroimaging studies and measurement of blood lactate are useful screening tests for the diagnosis of MELAS, though the definite diagnosis of MELAS relies on the ragged red fibers (RRFs) or strongly succinate dehydrogenase-stained vessels (SSVs) demonstrated by muscle biopsy, or the causative mtDNA mutation confirmed by molecular genetic studies. 10 In 1990, Goto et al 5 first identified the mtDNA A3243G mutation as the molecular basis of MELAS, which was shown to account for more than 80% of the MELAS patients. 11 However, at least 20 other distinct pathogenic mtDNA mutations have been reported in the other 20% patients with MELAS in the past two decades, 12 suggesting great heterogeneity in the genotype of MELAS.…”