2. Academic Validation
  3. NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals with Leigh-like Encephalomyopathy

NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals with Leigh-like Encephalomyopathy

  • Am J Hum Genet. 2018 Mar 1;102(3):460-467. doi: 10.1016/j.ajhg.2018.01.008.
Dorota Piekutowska-Abramczuk 1,  Zahra Assouline 2,  Lavinija Mataković 3,  René G Feichtinger 3,  Eliška Koňařiková 4,  Elżbieta Jurkiewicz 5,  Piotr Stawiński 6,  Mirjana Gusic 4,  Andreas Koller 3,  Agnieszka Pollak 7,  Piotr Gasperowicz 8,  Joanna Trubicka 1,  Elżbieta Ciara 1,  Katarzyna Iwanicka-Pronicka 9,  Dariusz Rokicki 10,  Sylvain Hanein 11,  Saskia B Wortmann 12,  Wolfgang Sperl 3,  Agnès Rötig 11,  Holger Prokisch 4,  Ewa Pronicka 13,  Rafał Płoski 14,  Giulia Barcia 2,  Johannes A Mayr 15
Affiliations

Affiliations

  • 1 Department of Medical Genetics, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
  • 2 Department of Genetics, Hôpital Necker-Enfants-Malades, 75015 Paris, France.
  • 3 Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
  • 4 Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • 5 Department of Diagnostic Imaging, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
  • 6 Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland; Department of Genetics, Institute of Physiology and Pathology of Hearing, 05-830 Warsaw/Kajetany, Poland.
  • 7 Department of Genetics, Institute of Physiology and Pathology of Hearing, 05-830 Warsaw/Kajetany, Poland.
  • 8 Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland.
  • 9 Department of Audiology and Phoniatrics, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
  • 10 Department of Paediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
  • 11 INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
  • 12 Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University Salzburg, 5020 Salzburg, Austria; Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
  • 13 Department of Medical Genetics, The Children's Memorial Health Institute, 04-730 Warsaw, Poland; Department of Paediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
  • 14 Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland. Electronic address: rploski@wp.pl.
  • 15 Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University Salzburg, 5020 Salzburg, Austria. Electronic address: h.mayr@salk.at.
PMID: 29429571 DOI: 10.1016/j.ajhg.2018.01.008
Abstract

Respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases. Clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies. To date, disease-causing variants in genes coding for 27 complex I subunits, including 7 mitochondrial DNA genes, and in 11 genes encoding complex I assembly factors have been reported. Here, we describe rare biallelic variants in NDUFB8 encoding a complex I accessory subunit revealed by whole-exome Sequencing in two individuals from two families. Both presented with a progressive course of disease with encephalo(cardio)myopathic features including muscular hypotonia, cardiac hypertrophy, respiratory failure, failure to thrive, and developmental delay. Blood lactate was elevated. Neuroimaging disclosed progressive changes in the basal ganglia and either brain stem or internal capsule. Biochemical analyses showed an isolated decrease in complex I enzymatic activity in muscle and fibroblasts. Complementation studies by expression of wild-type NDUFB8 in cells from affected individuals restored mitochondrial function, confirming NDUFB8 variants as the cause of complex I deficiency. Hereby we establish NDUFB8 as a relevant gene in childhood-onset mitochondrial disease.

Keywords

Leigh syndrome; NADH dehydrogenase; complex I; lactic acidosis; mitochondria; oxidative phosphorylation; respiratory chain.

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