International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

Wednesday 20 November

11:15 - 11:30 HRS

GENETIC AND PHYSIOLOGICAL PERTURBATIONS OF THE HOMOCYSTEINE AND FOLATE PATHWAYS IN A MOUSE MODEL OF HUMAN DISEASE

S Ernest
Case Western

Co-Authors: 2) Carter M, 3) Hosack A, 3) Rosenblatt D, 2) Ross E, 1) Nadeau J
Institutions: 1) Case Western Reserve University, 2) Cornell University, 3) McGill University

The homocysteine and folate pathways are involved in essential cellular functions and anomalies in these pathways are associated with common birth defects, including folate-responsive and folate-resistant neural tube defects (NTD), and common adult diseases. Previously we used expression and metabolic analysis of mice with a series of single gene mutations to show that the homocysteine and folate pathways are adversely affected in mice with partial protein deficiencies in the WNT and hedgehog signal transduction pathways. In the present study, we analyzed a single gene mouse mutant model, crooked tail (Cd), whose developmental defects are suppressed with a folate-supplemented diet. Crooked-tail mice model the human folate-responsive NTD, permitting an assessment of the ways in which dietary supplementations suppress the adverse developmental outcomes of single gene mutations. A combination of metabolic assays and expression profiles were used to survey wild-type, heterozygous and homozygous Cd mice on normal, folate-supplemented and folate-deficient diets. We found that diet had a greater impact than the mutation on homocysteine levels. Expression profiles revealed important modulation of genes in the homocysteine and folate pathways as well as genes involved in inflammatory response. A joint cluster analysis of metabolite levels, expression patterns, and dietary supplements provided insights into the mechanisms of folate responsiveness. These studies illustrate the ways in which gene expression and metabolic assays can be combined with perturbations of physiological and developmental systems to define the complex networks of functional interactions that relate genetic mutations with disease outcomes.


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