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SHR Neuro Krebs Kardio Lipid

Haack, TB; Gorza, M; Danhauser, K; Mayr, JA; Haberberger, B; Wieland, T; Kremer, L; Strecker, V; Graf, E; Memari, Y; Ahting, U; Kopajtich, R; Wortmann, SB; Rodenburg, RJ; Kotzaeridou, U; Hoffmann, GF; Sperl, W; Wittig, I; Wilichowski, E; Schottmann, G; Schuelke, M; Plecko, B; Stephani, U; Strom, TM; Meitinger, T; Prokisch, H; Freisinger, P.
Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening.
Mol Genet Metab. 2014; 111(3): 342-352.
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Autor/innen der Med Uni Graz:
Plecko Barbara

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Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneity it is almost impossible to diagnose OXPHOS patients on clinical grounds alone. Hence next generation sequencing (NGS) provides a distinct advantage over candidate gene sequencing to discover the underlying genetic defect in a timely manner. One recent example is the identification of mutations in MTFMT that impair mitochondrial protein translation through decreased formylation of Met-tRNA(Met). Here we report the results of a combined exome sequencing and candidate gene screening study. We identified nine additional MTFMT patients from eight families who were affected with Leigh encephalopathy or white matter disease, microcephaly, mental retardation, ataxia, and muscular hypotonia. In four patients, the causal mutations were identified by exome sequencing followed by stringent bioinformatic filtering. In one index case, exome sequencing identified a single heterozygous mutation leading to Sanger sequencing which identified a second mutation in the non-covered first exon. High-resolution melting curve-based MTFMT screening in 350 OXPHPOS patients identified pathogenic mutations in another three index cases. Mutations in one of them were not covered by previous exome sequencing. All novel mutations predict a loss-of-function or result in a severe decrease in MTFMT protein in patients' fibroblasts accompanied by reduced steady-state levels of complex I and IV subunits. Being present in 11 out of 13 index cases the c.626C>T mutation is one of the most frequent disease alleles underlying OXPHOS disorders. We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases. Copyright © 2013 Elsevier Inc. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing)
Adolescent -
Adult -
Child -
Child, Preschool -
Exome -
Female -
Genetic Association Studies -
Humans -
Hydroxymethyl and Formyl Transferases - genetics
Hydroxymethyl and Formyl Transferases - metabolism
Infant -
Infant, Newborn -
Leigh Disease - genetics
Leigh Disease - metabolism
Leigh Disease - pathology
Male -
Mitochondria - genetics
Mitochondria - pathology
Oxidative Phosphorylation -
Protein Biosynthesis -
RNA, Transfer, Met - genetics
Sequence Analysis, DNA -

Find related publications in this database (Keywords)
Mitochondrial translation
OXPHOS deficiency
Exome sequencing
Leigh syndrome
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