Novel mutations of ND genes in complex I deficiency associated with mitochondrial encephalopathy

Isolated Complex I (CI) deficiency, the most frequent cause of mitochondrial disease, is a clinically and genetically heterogeneous condition. Complex I is a giant multiheteromeric enzyme composed of seven ND subunits encoded by mitochondrial DNA (mtDNA) genes, and at least 38 subunits encoded by nuclear genes. To establish the contribution to human mitochondrial encephalopathy of ND versus nuclear gene mutations, we have been undertaking a systematic analysis of CI genes in a cohort of 46 adult and paediatric patients with biochemically defined CI defect. Sequence analysis of the entire mtDNA let us identify six patients with mutations in ND genes. The clinical presentations varied, from infantile Leigh syndrome, to childhood MELAS, to adult-onset encephalopathic syndromes of variable severity. Three of the mutations were not previously reported (3481G > A, 14600G > A and 13063G > A, in NDI, ND6 and ND5 genes, respectively) and were further investigated in mutant transmitochondrial cybrids. Tight correlation between mutation load and decrease in CI activity was observed in each of the three mutant cybrid lines, supporting the pathogenic role of the novel mutations. Structural studies on mutant cybrids showed impaired assembly or reduced stability of the holoenzyme complex. In our experience ND gene mutations are relatively common in CI-defective mitochondrial encephalopathy of both children and adults.