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

  • J Med Genet. 2012 Feb;49(2):83-9. doi: 10.1136/jmedgenet-2011-100577.
Tobias B Haack  1 ,  Florence Madignier ,  Martina Herzer ,  Eleonora Lamantea ,  Katharina Danhauser ,  Federica Invernizzi ,  Johannes Koch ,  Martin Freitag ,  Rene Drost ,  Ingo Hillier ,  Birgit Haberberger ,  Johannes A Mayr ,  Uwe Ahting ,  Valeria Tiranti ,  Agnes Rötig ,  Arcangela Iuso ,  Rita Horvath ,  Marketa Tesarova ,  Ivo Baric ,  Graziella Uziel ,  Boris Rolinski ,  Wolfgang Sperl ,  Thomas Meitinger ,  Massimo Zeviani ,  Peter Freisinger ,  Holger Prokisch
Affiliations
  • 1. Institute of Human Genetics, Technische Universität München, Munich, Germany.
PMID: 22200994 DOI: 10.1136/jmedgenet-2011-100577
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.