The Neuro Team
Eric Shoubridge, PhD
The genetics of mtDNA is completely different from Mendelian genetics because of the high ploidy of mtDNA and because it is inherited maternally. Most cells contain hundreds or thousands of copies of mtDNA. In patients with mitochondrial disease, pathogenic mtDNAs usually co-exist with wild-type mtDNAs (heteroplasmy). In general, the proportion of mutant mtDNAs must exceed a particular threshold to produce a biochemical phenotype, so the rules that govern the transmission of mtDNA in the female germline, and the segregation of mutant mtDNAs in different tissues during fetal and postnatal life, are important determinants of the expression of a pathogenic phenotype, specific tissue involvement, and the severity of disease. The factors affecting the transmission and segregation of pathogenic mtDNA mutants remain, however, poorly understood. Using biochemical and genetic approaches, we are investigating the structural organization of mtDNA, and the nature of the nuclear genetic factors that influence its transmission and segregation.
Most nuclear genetic effects affecting respiratory chain function are inherited as autosomal recessive traits. These are most prevalent in the pediatric population, where they are associated with severe respiratory chain dysfunction and an early fatal outcome. Using functional complementation cloning techniques in cell lines from patients, we are identifying and characterizing the genes associated with these disorders. The vast majority of these deficiencies result from an inability to assemble one or more of the respiratory chain complexes. This has led us to investigate the pathways of assembly of the individual enzyme complexes as well as the mitochondrial translation system that synthesizes the essential structural components encoded in mtDNA.