Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9.

TitleMutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9.
Publication TypeJournal Article
Year of Publication2012
AuthorsHaack, TB, Madignier, F, Herzer, M, Lamantea, E, Danhauser, K, Invernizzi, F, Koch, J, Freitag, M, Drost, R, Hillier, I, Haberberger, B, Mayr, JA, Ahting, U, Tiranti, V, Rötig, A, Iuso, A, Horvath, R, Tesarova, M, Baric, I, Uziel, G, Rolinski, B, Sperl, W, Meitinger, T, Zeviani, M, Freisinger, P, Prokisch, H
JournalJ Med Genet
Date Published2012 Feb
KeywordsDNA Mutational Analysis, Electron Transport Complex I, Genes, Mitochondrial, Genetic Heterogeneity, High-Throughput Screening Assays, Humans, Mitochondrial Diseases, Mutation, NADH Dehydrogenase, Phenotype

BACKGROUND: Mitochondrial complex I deficiency is the most common cause of mitochondrial disease in childhood. Identification of the molecular basis is difficult given the clinical and genetic heterogeneity. Most patients lack a molecular definition in routine diagnostics.METHODS: A large-scale mutation screen of 75 candidate genes in 152 patients with complex I deficiency was performed by high-resolution melting curve analysis and Sanger sequencing. The causal role of a new disease allele was confirmed by functional complementation assays. The clinical phenotype of patients carrying mutations was documented using a standardised questionnaire.RESULTS: Causative mutations were detected in 16 genes, 15 of which had previously been associated with complex I deficiency: three mitochondrial DNA genes encoding complex I subunits, two mitochondrial tRNA genes and nuclear DNA genes encoding six complex I subunits and four assembly factors. For the first time, a causal mutation is described in NDUFB9, coding for a complex I subunit, resulting in reduction in NDUFB9 protein and both amount and activity of complex I. These features were rescued by expression of wild-type NDUFB9 in patient-derived fibroblasts.CONCLUSION: Mutant NDUFB9 is a new cause of complex I deficiency. A molecular diagnosis related to complex I deficiency was established in 18% of patients. However, most patients are likely to carry mutations in genes so far not associated with complex I function. The authors conclude that the high degree of genetic heterogeneity in complex I disorders warrants the implementation of unbiased genome-wide strategies for the complete molecular dissection of mitochondrial complex I deficiency.

Alternate JournalJ. Med. Genet.
Citation Key10.1136/jmedgenet-2011-100577
PubMed ID22200994
Grant List096919 / / Wellcome Trust / United Kingdom
G1000848 / / Medical Research Council / United Kingdom
GPP10005 / / Telethon / Italy