The parent grant has its aims the elucidation of genetic, biochemical and pathogenetic aspects of metabolic disorders resulting in mental retardation (Stephen Goodman, P.I.). The applicant (Jan P. Kraus, Ph.D.) us a Project Leader in this program project grant and has developed this application to collaborate with Viktor Kozich, M.D., Ph.D. from Charles University in Prague, Czech Republic. The applicant proposes to determine the mechanisms of altered gene expression of the cystathionine b-synthase (CBS) gene in classical Homocystinuria (related to the Parent Grant) and also in patients with coronary/peripheral arterial disease (Homocysteine metabolism and atherosclerosis) in whom a mild hyperhomocystinemia is present. The purpose of the investigation is to define the molecular events related to the CBS gene that may be relevant to efficient diagnosis and treatment of these disorders. The applicant is focusing on the role of a frequent (5-9% of the population) polymorphism (844ins68bp allele in the CBS gene) with respect to the incidence of homocystinuria, the possible role of this allele in inducing a common mutation(1278T) that may also explain the incidence of disease and the impact of the allele mutation on the steady state of normal CBSmRNA in cultured fibroblasts. An extensive analysis of the mutations in the CBS gene will be evaluated from blood samples of patients with homocystinuria from abroad ad mutations have been shown to be differently distributed in various populations. Finally the applicant proposes to study how the mutations in regulatory portions of the CBS gene may have caused the low CBS expression leading to abnormal homocysteine metabolism.
|Vyletal, Petr; Sokolova, Jitka; Cooper, David N et al. (2007) Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion. Hum Mutat 28:255-64|
|Maclean, Kenneth N; Gaustadnes, Mette; Oliveriusova, Jana et al. (2002) High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations. Hum Mutat 19:641-55|
|Maclean, Kenneth N; Janosik, Miroslav; Kraus, Eva et al. (2002) Cystathionine beta-synthase is coordinately regulated with proliferation through a redox-sensitive mechanism in cultured human cells and Saccharomyces cerevisiae. J Cell Physiol 192:81-92|
|Linnebank, M; Homberger, A; Kraus, J P et al. (2001) Haplotyping of wild type and I278T alleles of the human cystathionine beta-synthase gene based on a cluster of novel SNPs in IVS12. Hum Mutat 17:350-1|
|Janosik, M; Oliveriusova, J; Janosikova, B et al. (2001) Impaired heme binding and aggregation of mutant cystathionine beta-synthase subunits in homocystinuria. Am J Hum Genet 68:1506-13|
|de Franchis, R; Kraus, E; Kozich, V et al. (1999) Four novel mutations in the cystathionine beta-synthase gene: effect of a second linked mutation on the severity of the homocystinuric phenotype. Hum Mutat 13:453-7|