Title | Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Haack, 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 |
Journal | J Med Genet |
Volume | 49 |
Issue | 2 |
Pagination | 83-9 |
Date Published | 2012 Feb |
ISSN | 1468-6244 |
Keywords | DNA Mutational Analysis, Electron Transport Complex I, Genes, Mitochondrial, Genetic Heterogeneity, High-Throughput Screening Assays, Humans, Mitochondrial Diseases, Mutation, NADH Dehydrogenase, Phenotype |
Abstract | 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. |
DOI | 10.1136/jmedgenet-2011-100577 |
Alternate Journal | J. Med. Genet. |
Citation Key | 10.1136/jmedgenet-2011-100577 |
PubMed ID | 22200994 |
Grant List | 096919 / / Wellcome Trust / United Kingdom G1000848 / / Medical Research Council / United Kingdom GPP10005 / / Telethon / Italy |