International Mammalian Genome Society

E6 Genetic, Molecular and Physiological Control of Folate and Homocysteine Metabolism: Hedgehog Signal Transduction Mutations Affect Homocysteine Levels and RNA Abundance Profiles

Sheila R. Ernest, Benedicte Christensen, Brian M. Gilfix, Orval A. Mamer, Patrick J. Dunn, Angela Hosack² Mitchell Rodier, Clemencia Colmenares, James McGrath, Allen Bale, Rudi Balling, David Sankoff, David S. Rosenblatt, and Joseph H. Nadeau. Department of Genetics, CWRU School of Medicine, Cleveland Center for Genome Research

Hyperhomocysteinemia is an important risk factor for premature cardiovascular disease, neural tube defects, and perhaps certain cancers and neurodegenerative diseases. We report identification of new mouse models of homocysteinemia and characterization of their molecular and physiological impact on folate and homocysteine metabolism. Several mutations in hedgehog signal transduction and lipid transport were associated with elevated homocysteine levels and with altered RNA abundance levels for several genes involved in folate and homocysteine metabolism. Cluster analysis of four of these mutants, their controls, and nine other strains revealed five groups of strains with similar expression profiles and homocysteine levels. Several genes showed contrasting RNA levels between strains with high versus intermediate or low homocysteine levels; several other genes showed consistent differences between the two groups with high homocysteine levels. These clusters may reflect criteria for predicting homocysteine and RNA abundance levels.