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.
- complex I
- Leigh syndrome
- homozygosity mapping
- candidate gene identification
- metabolic disorders
- molecular genetics
- muscle disease
- neuromuscular disease
- cell biology
- academic medicine
- diagnostics tests
- congenital heart disease
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BJCB and MG contributed equally to this work.
Funding This work was supported by an EU grant to the MitoCircle project (Sixth Framework Program, contr. no. 005260) and by the Alma in Silico project (EMR. INT4.-1.3.-2008-03/003). HP was supported by the Impulse & Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215), the German Network for Mitochondrial Disorders (mitoNET 01GM0862 and 01GM0867), and Systems Biology of Metabotypes (SysMBo 0315494A).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was performed within the diagnostic patient care at the Department of Clinical Genetics.
Provenance and peer review Not commissioned; externally peer reviewed.
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