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 trans-membrane 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.