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.
