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: 10.93). 05/1996; 58(5):933-9.
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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 second most common heteroplasmic point mutation is also on a tRNA gene. The m.8444A > G substitution in mt-tRNA Lys (Shoffner et al., 1990) mostly results in myoclonic epilepsy with ragged red fibers (MERFF) and is also linked to some cases of a MIDD-like syndrome (Santorelli et al., 1996a). Comparison of the m.32343A > G and m.8444A > G mutations highlights the clinical heterogeneity of mtDNA-related diseases, although both cause OXPHOS defects through a decreased protein synthesis rate (Yasukawa et al., 2000). "

    Turkish Journal of Biology 08/2015; 39:840-855. DOI:10.3906/biy-1505-20 · 1.34 Impact Factor
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    • "To date, mutations in LMNA, MYH7, MYBPC3, TNNT2, SCN5A, and MYH6 genes have been accounted for approximately 75% of FDCM [12]. Most of the genes implicated in genetics of DCM/FDCM follow autosomal dominant mode of inheritance [6], though a few follow autosomal recessive, X-linked [10], [13]–[16] and mitochondrial [16], [17]. Recent studies had suggested that the double and triple mutations identified in sarcomere protein genes were found to be associated with early onset of HCM [18], [19]. "
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    ABSTRACT: Cardiomyopathy is a major cause of heart failure and sudden cardiac death; several mutations in sarcomeric protein genes have been associated with this disease. Our aim in the present study is to investigate the genetic variations in Troponin T (cTnT) gene and its association with dilated cardiomyopathy (DCM) in south-Indian patients. Analyses of all the exons and exon-intron boundaries of cTnT in 147 DCM and in 207 healthy controls had revealed a total of 15 SNPs and a 5 bp INDEL; of which, polymorphic SNPs were compared with the HapMap population data. Interestingly, a novel R144W mutation, that substitutes polar-neutral tryptophan for a highly conserved basic arginine in cTnT, altering the charge drastically, was identified in a DCM, with a family history of sudden-cardiac death (SCD). This mutation was found within the tropomyosin (TPM1) binding domain, and was evolutionarily conserved across species, therefore it is expected to have a significant impact on the structure and function of the protein. Family studies had revealed that the R144W is co-segregating with disease in the family as an autosomal dominant trait, but it was completely absent in 207 healthy controls and in 162 previously studied HCM patients. Further screening of the proband and three of his family members (positive for R144W mutant) with eight other genes β-MYH7, MYBPC3, TPM1, TNNI3, TTN, ACTC, MYL2 and MYL3, did not reveal any disease causing mutation, proposing the absence of compound heterozygosity. Therefore, we strongly suggest that the novel R144W unique/private mutant identified in this study is associated with FDCM. This is furthermore signifying the unique genetic architecture of Indian population.
    PLoS ONE 07/2014; 9(7):e101451. DOI:10.1371/journal.pone.0101451 · 3.23 Impact Factor
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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.
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