GENETIC RISK FACTORS FOR HYPERHOMOCYSTEINEMIA

Summary

Principal Investigator: ROY GRAVEL
Abstract: It is now well established that elevated total plasma homocysteine is an independent risk factor for cardiovascular disease and that low folate shows association with increased risk for having a child with neural tube defects. Extrapolating from the central role played by a polymorphism of MTHFR in this process, we set out to clone genes and identify polymorphisms to determine if other genes involved in the metabolism of homocysteine would show such associations. A major outcome was the discovery of a novel enzyme methionine synthase reductase (gene and enzyme symbol, MTRR) required for the activation of cobalamin-dependent methionine synthase (MS). Through these experiments we detected a polymorphism, 66A>G (122M), present at a remarkable - aboutO.5 frequency, that appears to be associated with premature coronary artery disease, neural tube defects and Down syndrome. Significant progress included identification of mutations in severely affected patients with MTRR deficiency, modeling the 122M variant in the orthologous E. coli flavodoxin, and development of a mouse model of MTRR deficiency (founder heterozygotes confirmed). We hypothesize that the association of the 122M polymorphism with disease derives from structural and functional disturbances in the variant enzyme with impact on biochemical homeostasis and development. Accordingly, we propose the following specific aims to characterize the mechanism and physiological role of this novel enzyme and polymorphism: (1) Determine the biochemical impact of the 122M mutation in E. coil flavodoxin and humanMTRR. These studies will include biochemical characterization of 122 and M22 MTRR; assessment of FMN binding and domain interactions by 122M flavodoxin; and comparative crystal structure of 122M flavodoxin. (2) Characterize the phenotype of homozygous and heterozygous MTRR knock-out mice to gain understanding of the impact of severe and mild MTRR deficiency on physiology and development. We will examine the expression patterns of MS and MTRR during embryogenesis and in adult tissues by in-situ hybridization, Western blot and tissue immuno-fluorescence; evaluate levels of folate and methionine cycle metabolites in heterozygous and homozygous mutant mice, characterize the general pathology and behavioral phenotype of affected mice; evaluate vascular pathology and function; and explore nutrition-based treatment of homozygous mutant mice. In summary, our study will give a biochemical and physiological face to the impact of 122M on enzyme function, development and disease.
Funding Period: 1997-08-01 - 2006-11-30
more information: NIH RePORT

Top Publications

  1. pmc Human methionine synthase reductase is a molecular chaperone for human methionine synthase
    Kazuhiro Yamada
    4002 Life Sciences Institute, Department of Biological Chemistry, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109 2216, USA
    Proc Natl Acad Sci U S A 103:9476-81. 2006
  2. pmc Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development
    Nisha Padmanabhan
    Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
    Cell 155:81-93. 2013
  3. pmc Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase
    C Lee Elmore
    Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
    Mol Genet Metab 91:85-97. 2007
  4. pmc Restricted role for methionine synthase reductase defined by subcellular localization
    D S Froese
    Department of Biochemistry and Molecular Biology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alta, Canada T2N 4N1
    Mol Genet Metab 94:68-77. 2008

Detail Information

Publications4

  1. pmc Human methionine synthase reductase is a molecular chaperone for human methionine synthase
    Kazuhiro Yamada
    4002 Life Sciences Institute, Department of Biological Chemistry, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109 2216, USA
    Proc Natl Acad Sci U S A 103:9476-81. 2006
    ..Based on these findings, we propose that MSR serves as a special chaperone for hMS and as an aquacobalamin reductase, rather than acting solely in the reductive activation of MS...
  2. pmc Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development
    Nisha Padmanabhan
    Centre for Trophoblast Research, Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
    Cell 155:81-93. 2013
    ....
  3. pmc Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase
    C Lee Elmore
    Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
    Mol Genet Metab 91:85-97. 2007
    ..The different metabolite profiles in the various genetic mouse models for hyperhomocyst(e)inemia may be useful in understanding biological effects of elevated homocyst(e)ine...
  4. pmc Restricted role for methionine synthase reductase defined by subcellular localization
    D S Froese
    Department of Biochemistry and Molecular Biology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alta, Canada T2N 4N1
    Mol Genet Metab 94:68-77. 2008
    ..These data confirm that MSR protein is restricted to the cytosol but, based on the Leal study, suggest that a similar protein may interact with MMAB to reduce the mitochondrial cobalamin substrate in the generation of adenosylcobalamin...