High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine β-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.

Vascular and connective tissue features in 5 Italian patients with homocystinuria

“…This hypothesis is based on the association of connective tissue alterations with a group of missense mutations located in the CBS C-terminal region and affecting the domain interacting with S-adenosylmethionine (AdoMet), so an increase of AdoMet cannot further stimulate CBS production. Our 2 patients with a mutation in CBS regulatory domain, carried mild cardiovascular, skeletal and cutaneous stigmas, confirming the MacLean's hypothesis [15]. Overall, the presence of a mild connective tissue involvement, including heart valve alterations and striae distensae in all 5 patients, suggests that the connective tissue pathology in homocystinuria is relevant in relation to the cardiovascular manifestations which may become more severe with aging.…”

“…MacLean et al [15] suggested that clinical homocystinuric manifestations related to the connective tissue may be correlated to the decrease of CBS production causing both an increase of hcy levels and a decrease of cysteines. The decrease of cysteines may affect the qualitative and quantitative synthesis of connective tissue proteins causing EL and other connective tissue manifestations.…”

Potential Misdiagnosis of Hyperhomocysteinemia due to Cystathionine Beta-Synthase Deficiency During Pregnancy

“…Women with CBS deficiency are at increased risk for thrombosis during pregnancy and the literature documents CBS patients diagnosed, as was our patient, in the peripartum period (Kurczynski et al 1980;Constantine and Green 1987;Yap et al 2001;Levy et al 2002;Pierre et al 2006). Patients without severe connective tissue complications may present in adulthood (Maclean et al 2002;Magner et al 2011). In addition some patients are confused with Marfan Syndrome as was patient 1 (Berry and Levy 2010).…”

Spectrum of CBS mutations in 16 homocystinuric patients from the Iberian Peninsula: High prevalence of T191M and absence of I278T or G307S

“…Mutations at the C-terminal region are rare among homocystinuric patients. Recently, three C-terminal mutations have been described and their activity has been assayed by expressing them in E.coli [Maclean et al, 2002]. It was found that they were all 100% or more active but were unable to respond to AdoMet.…”