A MELAS syndrome family harboring two mutations in mitochondrial genome

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous mitochondrial disorder with variable clinical symptoms. Here, from the sequencing of the entire mitochondrial genome, we report a Korean MELAS family harboring two homoplasmic missense mutations, which were reported 9957T>C (Phe251Leu) transition mutation in the cytochrome c oxidase subunit 3 (COX3) gene and a novel 13849A>C (Asn505His) transversion mutation in the NADH dehydrogenase subunit 5 (ND5) gene. Neither of these mutations was found in 205 normal controls. Both mutations were identified from the proband and his mother, but not his father. The patients showed cataract symptom in addition to MELAS phenotype. We believe that the 9957T>C mutation is pathogenic, however, the 13849A>C mutation is of unclear significance. It is likely that the 13849A>C mutation might function as the secondary mutation which increase the expressivity of overlapping phenotypes of MELAS and cataract. This study also demonstrates the importance of full sequencing of mtDNA for the molecular genetic understanding of mitochondrial disorders.     

Systematic characterization of adenosine triphosphate response to lung cancer epidermal growth factor receptor missense mutations: A molecular insight into “generic” drug resistance mutations

Many missense mutations in human epidermal growth factor receptor (EGFR) are clinically involved in lung cancer and may cause acquired resistance to tyrosine kinase inhibitors. Traditionally, the resistance is considered to be established by impairing inhibitor affinity due to the mutations. However, it was found that, instead of blocking inhibitor binding, the gatekeeper mutation T790M can improve the kinase affinity for its natural substrate adenosine triphosphate (ATP), which is thus regarded as a “generic” resistance mutation that will reduce the potency of any ATP-competitive reversible kinase inhibitor. In this study, we attempt to systematically investigate the binding behavior of ATP to clinically observed EGFR missense mutants in nonsmall-cell lung cancer to identify those substantial mutations that may significantly increase (or decrease) ATP affinity. Several substantial mutations are excluded because they are also involved in kinase's catalytic activity or directly influence inhibitor binding, thus largely complicating the multiple dependent relationships of kinase, ATP, and inhibitor. Two new “generic” resistance mutations, A839T and E758G, are identified, which can improve ATP affinity by forming a favorable hydrogen bond and by eliminating unfavorable electrostatic effect between the kinase and ATP, respectively.