Mutations of the mitochondrial ND1 gene as a cause of MELAS

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes ( MELAS) is one of many clinical presentations associated with mutations in mitochondrial DNA ( mtDNA) and a biochemical deficiency of respiratory chain complex I. While the 'common' 3243A-->G mutation in the mitochondrial tRNA(Leu(UUR)) (MTTL1) gene is detected in approximately 80% of patients with MELAS, the aetiology of the remaining 20% is heterogeneous, with different causative mutations occurring in MTTL1, other mitochondrial tRNA (mt-tRNA) genes, and the MTND genes encoding subunits of complex I. We report three unrelated patients with MELAS in whom the 3243A-->G mutation could not be detected, but who expressed a specific deficiency of complex I activity in both skeletal muscle and cultured fibroblasts. Targeted sequencing of mt-tRNA and MTND genes revealed that each patient harboured a different novel mutation in the MTND1 subunit gene of complex I (3697G-->A, 3946G-->A, and 3949T-->C), each of which predicted an amino acid change. The failure to restore complex I activity upon fusion of patient cells with a cell line lacking mtDNA (rho(0) cells) confirmed pathogenicity for each of these mutations, all of which appear to perturb the assembly or turnover of complex I. Our finding of three novel mutations in the MTND1 gene causing MELAS is supportive of recent papers highlighting the importance of mtDNA mutations in the aetiology of childhood respiratory chain complex I deficiency and underlines the importance of a cohesive diagnostic strategy where molecular genetic investigations are shaped by the biochemical and histological findings.