Premium
High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine β‐synthase (CBS) mutations
Author(s) -
Maclean Kenneth N.,
Gaustadnes Mette,
Oliveriusová Jana,
Janošík Miroslav,
Kraus Eva,
Kožich Viktor,
Kery Vladimír,
Skovby Flemming,
Rüdiger Niels,
Ingerslev Jørgen,
Stabler Sally P.,
Allen Robert H.,
Kraus Jan P.
Publication year - 2002
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.10089
Subject(s) - homocystinuria , cystathionine beta synthase , missense mutation , homocysteine , biology , mutant , biochemistry , genetics , mutation , gene , methionine , amino acid
Cystathionine β‐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. Hum Mutat 19:641–655, 2002. © 2002 Wiley‐Liss, Inc.