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Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene (G8363A) Am J Hum Genet 58: 933-939

H. Houston Merritt Center for Muscular Research and Related Disorders, Department of Neurology, Columbia University 10032, New York, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 05/1996; 58(5):933-9.
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ABSTRACT A novel G8363A mutation in the mtDNA tRNA(Lys) gene was associated, in two unrelated families, with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The G8363A mutation was very abundant (>95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% +/- 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome (c) oxidase-negative fibers than in cytochrome (c) oxidase-positive fibers. The mutation was not found in >200 individuals, including normal controls and patients with other mitochondrial encephalomyopathies, thus fulfilling accepted criteria for pathogenicity.

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Available from: Ricardo E Madrid, Dec 02, 2014
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    • "The mutation m.16023G>A occurs at position 1 in mt-tRNA Pro (Fig. 2), and although to date, no other definitely pathogenic mutations have been identified at this position, m.8363G>A (mt-tRNA Lys ) does occur at its cognate pair [Ozawa et al., 1997; Santorelli et al., 1996]. Given the location of this mutation at the end of the acceptor stem, pathogenesis may result from disruption of either posttranscriptional processing of the mt-tRNA from the transcript, or aminoacylation. "
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    ABSTRACT: Mutations in the mitochondrial genome, and in particular the mt-tRNAs, are an important cause of human disease. Accurate classification of the pathogenicity of novel variants is vital to allow accurate genetic counselling for patients and their families. The use of weighted criteria based on functional studies - outlined in a validated pathogenicity scoring system - are therefore invaluable in determining whether novel or rare mt-tRNA variants are pathogenic. Here we describe the identification of 9 novel mt-tRNA variants in nine families, in which the probands presented with a diverse range of clinical phenotypes including mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), isolated progressive external ophthalmoplegia (PEO), epilepsy, deafness and diabetes. Each of the variants identified (m.4289T>C, MT-TI; m.5541C>T, MT-TW; m.5690A>G, MT-TN; m.7451A>T, MT-TS1; m.7554G>A, MT-TD; m.8304G>A, MT-TK; m.12206C>T, MT-TH; m.12317T>C, MT-TL2; m.16023G>A, MT-TP) was present in a different tRNA, with evidence in support of pathogenicity, and where possible, details of mutation transmission documented. Through the application of the pathogenicity scoring system, we have classified six of these variants as 'definitely pathogenic' mutations (m.5541C>T, m.5690A>G, m.7451A>T, m.12206C>T, m.12317T>C and m.16023G>A), whilst the remaining three currently lack sufficient evidence and are therefore classed as 'possibly pathogenic'(m.4289T>C, m.7554G>A and m.8304G>A). This article is protected by copyright. All rights reserved.
    Human Mutation 09/2013; 34(9). DOI:10.1002/humu.22358 · 5.05 Impact Factor
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    • "5545 tRNA Trp C→T http//www.mitmap.org,2010 8296 tRNA Lys A→G [52] 8348 tRNA Lys A→G [53] 8363 tRNA Lys G→A [54] "
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    Hereditas (Beijing) 06/2011; 33(6):549-57. DOI:10.3724/SP.J.1005.2011.00549
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    • "(A) MT5 MELAS family with m.3243A>G, (B) MT4 MELAS family with m.3271T>C, (C) MT10 MELAS family with m.10191T>C, (D) MT1 MERRF family with m.8344A>G, and (E) MT6 MERRF/PEO overlapping family with m.8344A>G. al., 1990, 1991, 1994; Shoffner et al., 1990; Silvestri et al., 1992; Santorelli et al., 1996; Taylor et al., 2001). Many MELAS and MERRF patients have shown one of these mtDNA mutations, however, no causative mutation has still been identified in a large part of patients. "
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