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Mol Genet Metab. 2014 Mar;111(3):342-52. doi: 10.1016/j.ymgme.2013.12.010. Epub 2013 Dec 25.

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

Author information

  • 1Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • 2Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 3Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
  • 4Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • 5Functional Proteomics, SFB 815 core unit, Faculty of Medicine, Goethe-University, 60590 Frankfurt am Main, Germany.
  • 6Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
  • 7Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands.
  • 8Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital, 69120 Heidelberg, Germany.
  • 9Department of Pediatrics and Pediatric Neurology, Universitätsmedizin Göttingen, 37075 Göttingen, Germany.
  • 10Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, 13125 Berlin, Germany.
  • 11Department of Neurology, Kinderspital Zürich, Zürich, Switzerland.
  • 12Department of Neuropediatrics, University Hospital, 24105 Kiel, Germany.
  • 13Department of Pediatrics, Inherited Metabolic Disease Centre, Klinikum Reutlingen, 72764 Reutlingen, Germany. Electronic address: freisinger_p@klin-rt.de.


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.


Exome sequencing; Leigh syndrome; MTFMT; Mitochondrial translation; OXPHOS deficiency

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