Research in the Molecular Pathogenesis Section is focused on defining genetic variations that underlie disease and understanding the mechanism by which these variant alleles produce disease. The total number of cloned human genes is increasing at an extreme rate; however, our ability to understand the function of these genes has not kept pace. An integrated approach, combining investigation into genetics (i.e., variation) and biology (i.e., function) is required if we make use of the wealth of data produced by the Human Genome Project.

Work in Dr. Brody's lab is exploring two contrasting model systems using this approach: the role of the BRCA1 and BRCA2 genes in inherited breast cancer susceptibility and the contribution of methionine synthase gene variation to disease. In the former system, the link between the gene(s) and a disease (cancer susceptibility) is well established but our knowledge of genotype-phenotype correlation and gene function is limited. Current research centers on BRCA1 functional and population biology. His laboratory discovered that a specific BRCA1 mutation is present at high frequency in the Ashkenazi Jewish population. They are studying this population in order to better understand the risk of cancer associated with these mutations.

In contrast with BRCA1 and BRCA2, much is known about the function of the methionine synthase (MS) protein but very little about its molecular biology, genetics and role of variation in human disease. The substrates and products (homocysteine and folate) of the MS reaction contribute the risk of cardiovascular disease, neural tube defects and vitamin B12 dependent anemia and neuropathy. The pathogenesis of these various disease states is poorly understood and collectively they represent a major public health concern. Dr. Brody's team is testing the hypothesis that inherited variations in the MS gene play a role in these processes.