Cystathionine beta-synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment

Abstract

Cystathionine beta-synthase (CBS) deficient homocystinuria is an inherited metabolic defect that if untreated typically results in mental retardation, thromboembolism and a range of connective tissue disturbances. A knockout mouse model has previously been used to investigate pathogenic mechanisms in classical homocystinuria (Watanabe et al., PNAS 92 (1995) 1585–1589). This mouse model exhibits a semi-lethal phenotype and the majority of mice do not survive the early neonatal period. We report here that the birth incidence of cbs (−/−) mice produced from heterozygous crosses is non-Mendelian and not significantly improved by treatment with either the Hcy lowering compound betaine or the cysteine donor N-acetylcysteine. Betaine treatment did improve survival of cbs (−/−) mice and restored fertility to female cbs (−/−) mice but did so without significantly lowering Hcy levels. Surviving cbs (−/−) mice failed to show any alteration in coagulation parameters compared to wild-type controls. Moribund cbs (−/−) mice exhibited severe liver injury and hepatic fibrosis while surviving cbs (−/−) mice although less severely affected, still exhibited a level of severe liver injury that is not found in the human disease. The hepatopathy observed in this model may offer an explanation for the failure of cbs (−/−) mice to respond to betaine or exhibit a hypercoagulative phenotype. We conclude that although this model provides useful data on the biochemical sequelae of classical homocystinuria, it does not successfully recapitulate a number of important features of the human disease and its use for studying mechanisms in homocystinuria should be treated with caution as the hepatopathy produces changes which could influence the results.

A functional variant in the cystathionine β-synthase gene promoter significantly reduces congenital heart disease susceptibility in a Han Chinese population

“…And among the CBSdeficient HCU patients or Cbs knockout mice, there were no reports that they were affected by CHD, although they had dramatically elevated plasma homocysteine levels [9,[25][26][27][28][29][30]. We presume that it reflects the different roles of transsulfuration pathway catalyzed by CBS and remethylation pathway by MTR/MTRR in homocyestine removal in different developmental stages.…”

“…In both Down syndrome children and the CBS transgenic mice, a significant decrease in plasma homocysteine levels was observed with the overexpression of CBS [20][21][22][23][24]. In contrast, both the patients with inherited homocystinuria caused by CBS deficiency and the Cbs knockout mice had significantly elevated plasma homocysteine levels [9,[25][26][27][28][29][30]. Therefore, the CBS expression level demonstrated a correlation with the plasma homocysteine levels, although in this study we did not observe a statistically significant difference in plasma homocysteine levels in 522 fasting undergraduates with different CBS −4673 genotypes.…”

“…However, the overloaded homocysteine due to CBS deficiency after birth could not be compensated anymore, and CBS activity undergoes dramatic change after birth to maintain normal plasma total homocysteine (tHcy) level. Thus, HCU patients and Cbs knockout mice had extremely high plasma tHcy levels without any CHD phenotype [9,[25][26][27][28][29][30]. On the other hand, the decreasing MTR/MTRR activity, which plays a vital role in homocysteine removal, could not be compensated either by CBS activity in the same cells or by hepatic BHMT before fetal liver formation on day 32.…”

Betaine treatment of cystathionine β-synthase-deficient homocystinuria; does it work and can it be improved?

“…55 Betaine treatment in the absence of dietary methionine restriction significantly decreased plasma tHcy levels (P , 0.0001) and concomitantly increased the clotting time in the HO mice (P = 0.0005). 56 Subsequent work has found that HO HCU mice exhibit a highly significant induction of the pro-inflammatory cytokines interleukin 1a (IL-1a), IL-1b, and tumor necrosis factor-α (TNF-α).…”

“…The failure of betaine treatment to lower Hcy in Cbs null mice is most likely due to the influence of severe liver injury upon hepatic BHMT expression. 55 The fact that betaine treatment significantly improved survival in Cbs null mice without significantly lowering tHcy indicates that this compound may Similarly, there was a 4-, 4.5-, 5.6-, and 4.7 -fold increase in plasma methionine, DMG, MG, and cysteine respectively (P , 0.0001 for all four metabolites) (Figure 2A and B). Lowering plasma tHcy by betaine treatment also resulted in a 40% decrease in plasma AdoMet (P = 0.0039) and a fivefold decrease in AdoHcy levels (P , 0.0001).…”