Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening

• Verfasst von: Haack, Tobias [VerfasserIn]
• Verfasst von: Kotzaeridou, Urania [VerfasserIn]
• Verfasst von: Hoffmann, Georg F. [VerfasserIn]
• Titel: Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening
• Verf.angabe: Tobias B. Haack, Matteo Gorza, Katharina Danhauser, Johannes A. Mayr, Birgit Haberberger, Thomas Wieland, Laura Kremer, Valentina Strecker, Elisabeth Graf, Yasin Memari, Uwe Ahting, Robert Kopajtich, Saskia B. Wortmann, Richard J. Rodenburg, Urania Kotzaeridou, Georg F. Hoffmann, Wolfgang Sperl, Ilka Wittig, Ekkehard Wilichowski, Gudrun Schottmann, Markus Schuelke, Barbara Plecko, Ulrich Stephani, Tim M. Strom, Thomas Meitinger, Holger Prokisch, Peter Freisinger
• Jahr: 2014
• Jahr des Originals: 2013
• Umfang: 11 S.
• Fussnoten: Program and abstracts for the 2014 meeting of the Society for Inherited Metabolic Disorders ; Gesehen am 29.01.2016 ; Available online 25 December 2013
• Titel Quelle: Enthalten in: Molecular genetics and metabolism
• Ort Quelle: Orlando, Fla. : Academic Press, 1998
• Jahr Quelle: 2014
• Band/Heft Quelle: 111(2014), 3, Seite 342-352
• ISSN Quelle: 1096-7206
• DOI: doi:10.1016/j.ymgme.2013.12.010
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Exome sequencing
• Sach-SW: Leigh syndrome
• Sach-SW: Mitochondrial translation
• Sach-SW: MTFMT
• Sach-SW: OXPHOS deficiency
• K10plus-PPN: 1524848360

Abstract

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-tRNAMet. 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.