The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNA<sup>Lys</sup> gene

Rossmanith, Walter; Raffelsberger, Thomas; Roka, Julia; Kornek, Barbara; Feucht, Martha; Bittner, Reginald E.

doi:10.1002/ana.10753

Cited by 22 publications

(14 citation statements)

References 16 publications

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“…After this initial description, other studies have shown that the A8344G mutation is responsible for most cases of MERRF 13 . In the years following the discovery of the A8344G mutation, three additional point mutations have also been found in patients with MERRF in the tRNA Lys gene of mtDNA as follows: T8356C, G8361A and G8363A 14,15,16 . The T8356C Figure 1.…”

Section: What Are the Genetic Abnormalities?mentioning

confidence: 99%

“…point mutation was found in patients with MERRF who also had stroke-like episodes, suggesting an overlap between MERRF and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) 16,17 . The A8361G point mutation was described in patients associated with MERRF manifesting with deafness and dementia 14 . The G8363A point mutation appears to be related to the presence of cardiomyopathy and deafness in patients with MERRF, and, in some cases, it overlap with Leigh syndrome 15,18,19,20 .…”

Section: What Are the Genetic Abnormalities?mentioning

confidence: 99%

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When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

Lorenzoni

Scola

Kay

et al. 2014

Arq. Neuro-Psiquiatr.

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Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disorder. Diagnostic criteria for MERRF include typical manifestations of the disease: myoclonus, generalized epilepsy, cerebellar ataxia and ragged red fibers (RRF) on muscle biopsy. Clinical features of MERRF are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNA Lys gene of the DNAmt, mainly A8344G, are responsible for almost 90% of MERRF cases. Morphological changes seen upon muscle biopsy in MERRF include a substantive proportion of RRF, muscle fibers showing a deficient activity of cytochrome c oxidase (COX) and the presence of vessels with a strong reaction for succinate dehydrogenase and COX deficiency. In this review, we discuss mainly clinical and laboratory manifestations, brain images, electrophysiological patterns, histology and molecular findings as well as some differential diagnoses and treatments.Keywords: MERRF, mitochondrial, epilepsy, myoclonus, myopathy. RESUMOEpilepsia mioclônica associada com fibras vermelhas rasgadas (MERRF) é uma rara doença mitocondrial. O critério diagnóstico para MERRF inclui as manifestações típicas da doença: mioclonia, epilepsia generalizada, ataxia cerebelar e fibras vermelhas rasgadas (RRF) na biópsia de músculo. Na fase inicial da doença, as manifestações clínicas podem não ser uniformes, e correlação entre as manifestações clínicas e fisiopatologia não estão completamente elucidadas. Estima-se que as mutações de ponto no gene tRNA Lys do DNAmt, principalmente a A8344G, sejam responsáveis por quase 90% dos casos de MERRF. As alterações morfológicas na biópsia muscular incluem uma grande proporção de RRF, fibras musculares com deficiência de atividade da citocromo c oxidase (COX) e presença de vasos com forte reação para succinato desidrogenase e deficiência da COX. Nesta revisão, são discutidas as principais manifestações clínicas e laboratoriais, imagens cerebrais, padrões eletrofisiológicos, histológicos e alterações moleculares, bem como, alguns dos diagnósticos diferenciais e tratamentos.

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Section: What Are the Genetic Abnormalities?mentioning

confidence: 99%

Section: What Are the Genetic Abnormalities?mentioning

confidence: 99%

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

Lorenzoni

Scola

Kay

et al. 2014

Arq. Neuro-Psiquiatr.

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“…often caused by numerous point mutations (G611A, A3243G, A8344G, G8361A, G12147A) in mtDNA, which affect genes encoding different mitochondrial tRNAs (Mancuso et al, 2004;Mongini et al, 2002;Shoffner et al, 1990;Rossmanith et al, 2003;Melone et al, 2004), is also to some extent associated with lipid-storage disorders and TG accumulation in muscles (MunozMalaga et al, 2000;Naumann et al, 1997). It has also been shown that most of multiple symmetrical lipomatosis (MSL) patients also display mitochondrial dysfunction Berkovic et al, 1991), lipomas that contain atypical multivacuolar white adipocytes (Zancanaro et al, 1990) as well as ragged red fibers and TG accumulation in muscles (Klopstock et al, 1997;Munoz-Malaga et al, 2000).…”

Section: Journal Of Cell Science 119 (7)mentioning

confidence: 99%

CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes

Vankoningsloo

Pauw

Houbion

et al. 2006

Journal of Cell Science

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Several mitochondrial pathologies are characterized by lipid redistribution and microvesicular cell phenotypes resulting from triglyceride accumulation in lipid-metabolizing tissues. However, the molecular mechanisms underlying abnormal fat distribution induced by mitochondrial dysfunction remain poorly understood. In this study, we show that inhibition of respiratory complex III by antimycin A as well as inhibition of mitochondrial protein synthesis trigger the accumulation of triglyceride vesicles in 3T3-L1 fibroblasts. We also show that treatment with antimycin A triggers CREB activation in these cells. To better delineate how mitochondrial dysfunction induces triglyceride accumulation in preadipocytes, we developed a low-density DNA microarray containing 89 probes, which allows gene expression analysis for major effectors and/or markers of adipogenesis. We thus determined gene expression profiles in 3T3-L1 cells incubated with antimycin A and compared the patterns obtained with differentially expressed genes during the course of in vitro adipogenesis induced by a standard pro-adipogenic cocktail. After an 8-day treatment, a set of 39 genes was found to be differentially expressed in cells treated with antimycin A, among them CCAAT/enhancer-binding protein α (C/EBPα), C/EBP homologous protein-10 (CHOP-10), mitochondrial glycerol-3-phosphate dehydrogenase (GPDmit), and stearoyl-CoA desaturase 1 (SCD1). We also demonstrate that overexpression of two dominant negative mutants of the cAMP-response element-binding protein CREB (K-CREB and M1-CREB) and siRNA transfection, which disrupt the factor activity and expression, respectively, inhibit antimycin-A-induced triglyceride accumulation. Furthermore, CREB knockdown with siRNA also downregulates the expression of several genes that contain cAMP-response element (CRE) sites in their promoter, among them one that is potentially involved in synthesis of triglycerides such as SCD1. These results highlight a new role for CREB in the control of triglyceride metabolism during the adaptative response of preadipocytes to mitochondrial dysfunction.

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“…These findings indicate that there is a respiratory chain dysfunction in the lipomas, and that lipomas may be a manifestation of the A8344G mutation. 58 In tRNA Lys gene four other mutations has also been associated with a typical MERRF phenotype: A8296G, 59 T8356C, 60 G8361A, 61 and G8363A. 59,62 However, the typical MERRF syndrome is not always associated with tRNA Lys mutations.…”

Section: The Clinical Phenotypes Of Mitochondrial Trna Mutationsmentioning

confidence: 99%

Mitochondrial tRNA Mutations: Clinical and Functional Perturbations

Zifa

Giannouli²,

Theotokis³

et al. 2007

RNA Biology

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The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNA^Lys gene

Cited by 22 publications

References 16 publications

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes

Mitochondrial tRNA Mutations: Clinical and Functional Perturbations

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The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNALys gene

Cited by 22 publications

References 16 publications

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

When should MERRF (myoclonus epilepsy associated with ragged-red fibers) be the diagnosis?

CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes

Mitochondrial tRNA Mutations: Clinical and Functional Perturbations

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About

The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNA^Lys gene