title: High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations.
abstract: Cystathionine beta-synthase (CBS) is a crucial regulator of plasma levels of the thrombogenic amino acid homocysteine (Hcy). Homocystinuria due to CBS deficiency confers a dramatically increased risk of thrombosis. Early diagnosis usually occurs after the observation of ectopia lentis, mental retardation, or characteristic skeletal abnormalities. Homocystinurics with this phenotype typically carry mutations in the catalytic region of the protein that abolish CBS activity. We describe a novel class of missense mutations consisting of I435T, P422L, and S466L that are located in the non-catalytic C-terminal region of CBS that yield enzymes that are catalytically active but deficient in their response to S-adenosylmethionine (AdoMet). The P422L and S466L mutations were found in patients suffering premature thrombosis and homocystinuric levels of Hcy but lacking any of the connective tissue disorders typical of homocystinuria due to CBS deficiency. The P422L and S466L mutants demonstrated a level of CBS activity comparable to that of the AdoMet stimulated wild-type CBS but could not be further induced by the addition of AdoMet. In terms of temperature stability, oligomeric organization, and heme saturation the I435T, P422L, and S466L mutants are indistinguishable from wild-type CBS. Our findings illustrate the importance of AdoMet for the regulation of Hcy metabolism and are consistent with the possibility that the characteristic connective tissue disturbances observed in homocystinuria due to CBS deficiency may not be due to elevated Hcy.
authors: Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA.
authors: Kenneth N
authors: KN
authors: Maclean
authors: Mette
authors: M
authors: Gaustadnes
authors: Jana
authors: J
authors: Oliveriusová
authors: Miroslav
authors: M
authors: Janosík
authors: Eva
authors: E
authors: Kraus
authors: Viktor
authors: V
authors: Kozich
authors: Vladimír
authors: V
authors: Kery
authors: Flemming
authors: F
authors: Skovby
authors: Niels
authors: N
authors: Rüdiger
authors: Jørgen
authors: J
authors: Ingerslev
authors: Sally P
authors: SP
authors: Stabler
authors: Robert H
authors: RH
authors: Allen
authors: Jan P
authors: JP
authors: Kraus
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D003238:Connective Tissue / Q000201:enzymology* / Q000473:pathology*; D006224:Cricetinae; D003412:Cricetulus; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D004252:DNA Mutational Analysis / Q000379:methods; D004795:Enzyme Stability / Q000235:genetics; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D012436:S-Adenosylmethionine / Q000378:metabolism / Q000502:physiology; D013927:Thrombosis / Q000201:enzymology*
chemical_list: D006710:Homocysteine; D012436:S-Adenosylmethionine; D003541:Cystathionine beta-Synthase