2. Academic Validation
  3. Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency

Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency

  • Am J Hum Genet. 2020 Jan 2;106(1):92-101. doi: 10.1016/j.ajhg.2019.12.001.
Charlotte L Alston 1,  Mike T Veling 2,  Juliana Heidler 3,  Lucie S Taylor 4,  Joseph T Alaimo 5,  Andrew Y Sung 6,  Langping He 1,  Sila Hopton 1,  Alexander Broomfield 7,  Julija Pavaine 8,  Jullianne Diaz 9,  Eyby Leon 9,  Philipp Wolf 10,  Robert McFarland 1,  Holger Prokisch 11,  Saskia B Wortmann 12,  Penelope E Bonnen 5,  Ilka Wittig 13,  David J Pagliarini 14,  Robert W Taylor 15
Affiliations

Affiliations

  • 1 Wellcome Centre for Mitochondrial Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; NHS Highly Specialised Services for Rare Mitochondrial Disorders, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.
  • 2 Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Functional Proteomics, Goethe-Universität, Frankfurt am Main, 60590 Frankfurt, Germany.
  • 4 Wellcome Centre for Mitochondrial Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
  • 5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6 Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • 7 Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK.
  • 8 Academic Unit of Paediatric Radiology, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester, M13 9WL, UK; Division of Informatics, Imaging, and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
  • 9 Rare Disease Institute, Children's National Hospital, Washington, DC 20010, USA.
  • 10 DRK Kinderklinik, Siegen, Wellersbergstraße 60, 57072 Siegen, Germany.
  • 11 Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 12 Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Department of Pediatrics, Salzburger Landeskliniken (SALK), Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
  • 13 Functional Proteomics, Goethe-Universität, Frankfurt am Main, 60590 Frankfurt, Germany; German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, 60590 Frankfurt, Germany.
  • 14 Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: [email protected].
  • 15 Wellcome Centre for Mitochondrial Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; NHS Highly Specialised Services for Rare Mitochondrial Disorders, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK. Electronic address: [email protected].
PMID: 31866046 DOI: 10.1016/j.ajhg.2019.12.001
Abstract

Leigh syndrome is one of the most common neurological phenotypes observed in pediatric mitochondrial disease presentations. It is characterized by symmetrical lesions found on neuroimaging in the basal ganglia, thalamus, and brainstem and by a loss of motor skills and delayed developmental milestones. Genetic diagnosis of Leigh syndrome is complicated on account of the vast genetic heterogeneity with >75 candidate disease-associated genes having been reported to date. Candidate genes are still emerging, being identified when "omics" tools (genomics, proteomics, and transcriptomics) are applied to manipulated cell lines and cohorts of clinically characterized individuals who lack a genetic diagnosis. NDUFAF8 is one such protein; it has been found to interact with the well-characterized complex I (CI) assembly factor NDUFAF5 in a large-scale protein-protein interaction screen. Diagnostic next-generation sequencing has identified three unrelated pediatric subjects, each with a clinical diagnosis of Leigh syndrome, who harbor bi-allelic pathogenic variants in NDUFAF8. These variants include a recurrent splicing variant that was initially overlooked due to its deep-intronic location. Subject fibroblasts were found to express a complex I deficiency, and lentiviral transduction with wild-type NDUFAF8-cDNA ameliorated both the assembly defect and the biochemical deficiency. Complexome profiling of subject fibroblasts demonstrated a complex I assembly defect, and the stalled assembly intermediates corroborate the role of NDUFAF8 in early complex I assembly. This report serves to expand the genetic heterogeneity associated with Leigh syndrome and to validate the clinical utility of orphan protein characterization. We also highlight the importance of evaluating intronic sequence when a single, definitively pathogenic variant is identified during diagnostic testing.

Keywords

NDUFAF8; complex I deficiency; mitochondrial disease; molecular diagnosis.

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