title: Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency.
abstract: Mitochondrial complex I deficiency is the most common defect of the OXPHOS system. We report a patient from consanguineous parents with a complex I deficiency expressed in skin fibroblasts. Homozygosity mapping revealed several homozygous regions with candidate genes, including the gene encoding an assembly factor for complex I, NDUFAF2. Screening of this gene on genomic DNA revealed a homozygous stop-codon resulting in a truncation of the protein at position 38. The mutation causes a severely reduced activity and a disturbed assembly of complex I. A baculovirus containing the GFP-tagged wild-type NDUFAF2 gene was used to prove the functional consequences of the mutation. The expression and activity of complex I was almost completely rescued by complementation of the patient fibroblasts with the baculovirus. Therefore, the homozygous substitution in NDUFAF2 is the disease-causing mutation, which results in a complex I deficiency in the fibroblasts of the patient.
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Saskia J G
authors.initials: SJ
authors.lastname: Hoefs
authors.forename: Cindy E J
authors.initials: CE
authors.lastname: Dieteren
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Karin
authors.initials: K
authors.lastname: Naess
authors.forename: Helene
authors.initials: H
authors.lastname: Bruhn
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.forename: Esther
authors.initials: E
authors.lastname: Wagena
authors.forename: Peter H
authors.initials: PH
authors.lastname: Willems
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Leo G
authors.initials: LG
authors.lastname: Nijtmans
authors.forename: Lambert P
authors.initials: LP
authors.lastname: van den Heuvel
mesh_terms: D016367:Baculoviridae / Q000235:genetics; D018389:Codon, Nonsense; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D007223:Infant; D024101:Mitochondrial Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D012867:Skin / Q000473:pathology
chemical_list: D018389:Codon, Nonsense; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; C501824:NDUFAF2 protein, human; D042967:Electron Transport Complex I