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Molecular Basis of Inherited Human Diseases 

My laboratory studies the molecular basis of two inherited metabolic disorders associated with deficiency of cystathionine β-synthase (CBS) and propionyl CoA carboxylase (PCC).

CBS is a crucial regulator of serum levels of the thrombogenic amino acid homocysteine (Hcy) and is crucial for the tissue specific biosynthesis of cysteine. CBS deficiency is the most common cause of homocystinuria, an inherited autosomal recessive metabolic disease that if untreated, causes skeletal abnormalities, dislocated optic lenses, mental retardation and a dramatically increased incidence of thromboembolic disease. Mildly elevated plasma Hcy in humans has also been identified as an independent risk factor for cardiovascular and thromboembolic disease. Increasing numbers of epidemiological studies are also finding an association between elevated Hcy and neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. The crucial role of CBS in the regulation of plasma Hcy has lead to increasing interest in the mechanisms that regulate this enzyme and the cellular consequences of its dysfunction. Currently, we are applying a range of approaches including functional genomics, transgenic mouse models, X-ray crystallography, molecular cell biology and protein biochemistry to investigate the etiology of the various disease states associated with elevated Hcy due to impaired CBS activity.

PCC is a mitochondrial enzyme comprised of non-identical subunits encoded on different chromosomes. Deficiency of PCC causes propionic acidemia. This condition is an autosomal recessive trait that is often life threatening in neonates. Recent research has indicated that in certain populations the incidence of this disease is far higher than previous estimates. Our research in this area is focused on improving our understanding of the molecular mechanisms that underlie the highly variable correlation between genotype and phenotype in propionic acidemia. To this end, we have developed a recombinant expression system using molecular chaperones that allows us to assess the effects of specific mutations upon PCC function. Adaptation of this system for large-scale expression of the human PCC holoenzyme in E.coli will facilitate characterization of the PCC enzyme complex using both spectroscopic and X-ray diffraction studies. We are currently identifying the promoter regions of both PCC genes to elucidate how PCC activity is regulated and to perform a functional analysis of the sequences that determine basal promoter activity in the human PCC genes. Techniques employed include the use of reporter constructs in luciferase assays, site directed mutagenesis, mammalian tissue culture, immunohistochemistry, band shift analysis and DNA footprinting.