The mitochondrial respiratory chain disorders (RCDs) collectively represent the most common inborn errors of metabolism.  These disorders are characterized by a biochemical defect in the electron transport chain.  While causal mutations in the mitochondrial genome (mtDNA) have been identified over the past 20 years, recent studies have shown that the majority of RCDs are actually due to mutations in the nuclear genome.  Availability of the complete sequence of the genome now provides a special opportunity to identify the molecular basis for these disorders.

Our laboratory has developed “integrative genomics” strategies to discover genes underlying these disorders.  For example, we combined evidence from genome-scale profiles of RNA and protein expression to pinpoint LRPPRC as the gene underlying Leigh Syndrome French Canadian Variant (LSFC).  LSFC is an autosomal recessive disease characterized by cytochrome c oxidase deficiency as well as Leigh disease.  LRPPRC encodes an mRNA binding protein that is located in the mitochondrion a well as in other compartments, and suggests a fundamentally new mechanism in mitochondrial pathogenesis.  More recently, we developed a Bayesian approach to integrate eight, genome-scale datasets to spotlight the gene underlying hepatocerebral mtDNA depletion syndrome, an autosomal recessive affecting children in  Italy.  The gene mutated in this disorder, MPV17, encodes a protein whose function is not well understood.  In both cases our results have translated into clinical genetic assays that can be used for carrier testing.  Our computational approaches are generic in nature and have assisted other groups to discover other genes underlying fatal, pediatric diseases as well.

We are currently using functional genomics to explore the pathogenesis of monogenic mitochondrial diseases, with the long-term goal of illuminating cellular pathways that may be useful in the diagnosis and treatment of these disorders.