2. Academic Validation
  3. NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect

NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect

  • Eur J Hum Genet. 2017 Nov;25(11):1273-1277. doi: 10.1038/ejhg.2017.133.
Fabian Baertling 1 2,  Laura Sánchez-Caballero 1,  Mariël A M van den Brand 1,  Liesbeth T Wintjes 1,  Maaike Brink 1,  Frans A van den Brandt 1,  Callum Wilson 3,  Richard J T Rodenburg 1,  Leo G J Nijtmans 1
Affiliations

Affiliations

  • 1 Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 2 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Heinrich Heine University, Dusseldorf, Germany.
  • 3 National Metabolic Service, Starship Children's Hospital, Auckland, New Zealand.
PMID: 28853723 DOI: 10.1038/ejhg.2017.133
Abstract

Mitochondrial respiratory chain complex I consists of 44 different subunits and can be subgrouped into three functional modules: the Q-, the P- and the N-module. NDUFAF4 (C6ORF66) is an assembly factor of complex I that associates with assembly intermediates of the Q-module. Via exome sequencing, we identified a homozygous missense variant in a complex I-deficient patient with Leigh syndrome. Supercomplex analysis in patient fibroblasts revealed specifically altered stoichiometry. Detailed assembly analysis of complex I, indicative of all of its assembly routes, showed an accumulation of parts of the P- and the N-module but not the Q-module. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and the assembly defect, confirming the causal role of the variant. Our report on the second family affected by an NDUFAF4 variant further characterizes the phenotypic spectrum and sheds LIGHT into the role of NDUFAF4 in mitochondrial complex I biogenesis.

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