Accurate molecular genetic diagnosis of patients with known mtDNA point mutations and recognition of patients with new mutations remain of central importance for the program Project as a whole. Thus, we will provide a molecular dimension to Project #1 by assessing the mutational load in accessible tissues from patients and oligosymptomatic maternal family members and by following potential drifts in heteroplasmy with time. In looking for new mutations, our emphasis will shift from those affecting mitochondrial protein synthesis to those involving polypeptide-encoding genes, because recent experience has taught us that disorders due to these genetic defects have been largely overlooked. Mutations in genes encoding subunits of complex I, complex III, or complex IV may be associated with tissue-specific of multi-systemic disorders, which often escape canonical rules of mitochondrial genetics. We will focus on three such mutations (in COX I, COX III, and ND5) causing encephalomyopathies, attempting to define their pathogenetic mechanisms through biochemical and immunohistochemical (collaboration with Project #5) analyses of tissues, and by measuring ATP production in cybrid cell lines In contrast to the rapid pace at which mtDNA mutations have been described in the past ten years, research on nuclear DNA mutations have been described in the past ten years, research on nuclear DNA mutations responsible for respiratory chain defects is just starting. We have had a long-standing interest in cytochrome c oxidase (COX) deficiency, the most common cause of Leigh syndrome (LS), and have collected a rich bank of tissues from patients. The recent identification of mutations in SURF1, gene encoding a COX-assembly protein, clarifies the molecular basis of some but not all cases of COS-deficient LS. Besides screening our patients for known and unknown mutations in SURF1, we will search for mutations in other genes encoding the numerous factors needed for proper assembly and function of human COX.
Showing the most recent 10 out of 241 publications
