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Am J Hum Genet. 2016 Feb 4;98(2):358-62. doi: 10.1016/j.ajhg.2015.12.009. Epub 2016 Jan 21.

Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy.

Author information

1
Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
2
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
3
Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
4
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
5
Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany; DZNE - German Center for Neurodegenerative Diseases, 80336 Munich, Germany.
6
University Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
7
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
8
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
9
Max-Planck-Institute for Molecular Genetics, Otto-Warburg Laboratory, 14195 Berlin, Germany; CU Systems Medicine, University of Würzburg, 97080 Würzburg, Germany.
10
Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
11
Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. Electronic address: meitinger@helmholtz-muenchen.de.

Abstract

Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different bi-allelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. TANGO2 (transport and Golgi organization 2) encodes a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in Drosophila and a mitochondrial localization has been confirmed in mice. Investigation of palmitate-dependent respiration in mutant fibroblasts showed evidence of a functional defect in mitochondrial β-oxidation. Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multi-organ involvement.

PMID:
26805782
PMCID:
PMC4746337
DOI:
10.1016/j.ajhg.2015.12.009
[Indexed for MEDLINE]
Free PMC Article

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