Novel mutation of ND4 gene identified by targeted next-generation sequencing in patient with Leigh syndrome

By using next-generation sequencing targeted to MitoExome including the entire mtDNA and exons of 1033 genes encoding the mitochondrial proteome, we described here a novel m. 11240C>T mutation in the mitochondrial ND4 gene from a patient with Leigh syndrome. High mutant loads of m. 11240C>T were detected in blood, urinary epithelium, oral mucosal epithelium cells, and skin fibroblasts of the patient. Decreased mitochondrial complex I activity was found in transmitochondrial cybrids containing the m. 11240C>T mutation with biochemical analysis. Furthermore, functional investigations confirmed that mitochondria with the m. 11240C>T variant exhibited lower adenosine triphosphate-related mitochondrial respiration. However, complex I assembly in mutant cybrids was not affected. While this mutation was located in the fourth hydrophobic transmembrane region of ND4 gene, we suggested that mutation of m. 11240C>T might impair the proton pumping channel of complex I but had little effect on the complex I assembly. In conclusion, we identified m. 11240C>T as a novel mitochondrial disease-related mtDNA mutation.