title: Genetic and molecular control of folate-homocysteine metabolism in mutant mice.
abstract: Hyperhomocysteinemia adversely affects fundamental aspects of fetal development, adulthood, and aging, but the role of elevated homocysteine levels in these birth defects and adult diseases remains unclear. Mouse models are valuable for investigating the causes and consequences of hyperhomocysteinemia. We used a phenotype-based approach to identify mouse mutants for studying the relation between single gene mutations, homocysteine levels as a measure of the status of homocysteine metabolism, and gene expression profiles as a way to assess the impact of protein deficiency in mutant mice on steady-state transcription levels of genes in the folate-homocysteine pathways. These mutants were selected based on their propensity to produce phenotypes that are reminiscent of those associated with anomalies in folate-homocysteine metabolism in humans. We report identification of new, single-gene mouse models of homocysteinemia and characterization of their molecular and physiological impact on folate-homocysteine metabolism. Mutations in several genes involved in the hedgehog and WNT signal transduction pathways, as well as a gene involved in lipid metabolism, resulted in elevated homocysteine levels and altered expression profiles of folate-homocysteine metabolism genes. These results begin to unravel the complex relations between elevation of a single amino acid in the blood and the diverse birth defects and adult diseases associated with hyperhomocysteinemia.
authors.affiliation: Department of Genetics, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Ernest
authors.forename: Benedicte
authors.initials: B
authors.lastname: Christensen
authors.forename: Brian M
authors.initials: BM
authors.lastname: Gilfix
authors.forename: Orval A
authors.initials: OA
authors.lastname: Mamer
authors.forename: Angela
authors.initials: A
authors.lastname: Hosack
authors.forename: Mitchell
authors.initials: M
authors.lastname: Rodier
authors.forename: Clemencia
authors.initials: C
authors.lastname: Colmenares
authors.forename: James
authors.initials: J
authors.lastname: McGrath
authors.forename: Allen
authors.initials: A
authors.lastname: Bale
authors.forename: Rudi
authors.initials: R
authors.lastname: Balling
authors.forename: David
authors.initials: D
authors.lastname: Sankoff
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Nadeau
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D004195:Disease Models, Animal; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008764:Methylmalonic Acid / Q000097:blood; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics
chemical_list: D006710:Homocysteine; D008764:Methylmalonic Acid; D005492:Folic Acid