Sequence analysis of nuclear genes encoding functionally important complex I subunits in children with encephalomyopathy

Complex I has a vital role in the energy production of the cell, and the clinical spectrum of complex I deficiency varies from severe lactic acidosis in infants to muscle weakness in adults. It has been estimated that the cause of complex I deficiency, especially in children, is often a mutation in the nuclear-encoded genes and, more rarely, in the genes encoded by mitochondrial DNA. We sequenced nine complex I subunit coding genes, NDUFAB1, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1 and NDUFV2, in 13 children with defined complex I deficiency. Two novel substitutions were found: a synonymous replacement 201A > T in NDUFV2 and a non-synonymous base exchange 52C > T in NDUFS8. The 52C > T substitution produced the replacement Arg18Cys in the leading peptide of the TYKY subunit. This novel missense mutation was found as a heterozygote in one patient and her mother, but not among 202 healthy controls nor among 107 children with undefined encephalomyopathy. Bioinformatic analyses suggested that Arg18Cys could lead to marked changes in the physicochemical properties of the mitochondrial-targeting peptide of TYKY, but we could not see changes in the assembly or activity of complex I or in the transcription of NDUFS8 in the fibroblasts of our patient. We suggest that Arg18Cys in the leading peptide of the TYKY subunit is not solely pathogenic, and that other genetic factors contribute to the disease-causing potential of this mutation.