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van den Bosch, B.J.* ; Gerards, M.* ; Sluiter, W.* ; Stegmann, A.P.* ; Jongen, E.L.* ; Hellebrekers, D.M.* ; Oegema, R.* ; Lambrichs, E.H.* ; Prokisch, H. ; Danhauser, K. ; Schoonderwoerd, K.* ; de Coo, I.F.* ; Smeets, H.J.*

Defective NDUFA9 as a novel cause of neonatally fatal complex I disease.

J. Med. Genet. 49, 10-15 (2012)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
BACKGROUND: Mitochondrial disorders are associated with abnormalities of the oxidative phosphorylation (OXPHOS) system and cause significant morbidity and mortality in the population. The extensive clinical and genetic heterogeneity of these disorders due to a broad variety of mutations in several hundreds of candidate genes, encoded by either the mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), impedes a straightforward genetic diagnosis. A new disease gene is presented here, identified in a single Kurdish patient born from consanguineous parents with neonatally fatal Leigh syndrome and complex I deficiency. METHODS AND RESULTS: Using homozygosity mapping and subsequent positional candidate gene analysis, a total region of 255.8 Mb containing 136 possible mitochondrial genes was identified. A pathogenic mutation was found in the complex I subunit encoding the NDUFA9 gene, changing a highly conserved arginine at position 321 to proline. This is the first disease-causing mutation ever reported for NDUFA9. Complex I activity was restored in fibroblasts of the patient by lentiviral transduction with wild type but not mutant NDUFA9, confirming that the mutation causes the complex I deficiency and related disease. CONCLUSIONS: The data show that homozygosity mapping and candidate gene analysis remain an efficient way to detect mutations even in small consanguineous pedigrees with OXPHOS deficiency, especially when the enzyme deficiency in fibroblasts allows appropriate candidate gene selection and functional complementation.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Secondary structure prediction; Mitochondrial-DNA mutations; Leigh-syndrome; Genetic diagnosis; Subunit; Patient; Disorders; Server; ACAD9
ISSN (print) / ISBN 0022-2593
e-ISSN 1468-6244
Journal Journal of Medical Genetics
Quellenangaben Volume: 49, Issue: 1, Pages: 10-15 Article Number: , Supplement: ,
Publisher BMJ Publishing Group
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)