De novo mutations in the mitochondrial <i>ND3</i> gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency

TLDR

Energy generation disorders arise from nuclear or mitochondrial DNA mutations, with complex I deficiency being the most common and typically attributed to nuclear genes, though recent evidence shows mitochondrial subunits ND4, ND5, and ND6 also cause infantile mitochondrial encephalopathies. We report the first four cases of infantile mitochondrial encephalopathies caused by mutations in the ND3 subunit gene. The study identified a novel heteroplasmic T10158C mutation in three unrelated infants and a previously reported T10191C mutation, both producing disproportionately greater reductions in complex I activity than assembly, indicating a critical role for ND3 and suggesting that de novo mitochondrial DNA mutations may be more common in pediatric complex I deficiency than previously thought.

Abstract

Both nuclear and mitochondrial DNA mutations can cause energy generation disorders. Respiratory chain complex I deficiency is the most common energy generation disorder and a frequent cause of infantile mitochondrial encephalopathies such as Leigh's disease and lethal infantile mitochondrial disease. Most such cases have been assumed to be caused by nuclear gene defects, but recently an increasing number have been shown to be caused by mutations in the mitochondrially encoded complex I subunit genes ND4, ND5, and ND6. We report the first four cases of infantile mitochondrial encephalopathies caused by mutations in the ND3 subunit gene. Three unrelated children have the same novel heteroplasmic mutation (T10158C), only the second mutation reported in ND3, and one has the previously identified T10191C mutation. Both mutations cause disproportionately greater reductions in enzyme activity than in the amount of fully assembled complex I, suggesting the ND3 subunit plays an unknown but important role in electron transport, proton pumping, or ubiquinone binding. Three cases appear to have a de novo mutation, with no mutation detected in maternal relatives. Mitochondrial DNA disease may be considerably more prevalent in the pediatric population than currently predicted and should be considered in patients with infantile mitochondrial encephalopathies and complex I deficiency.