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Cystathionine β-synthase (CBS) Deficiency: Genetics

  1. Viktor Kožich1,
  2. Warren D Kruger2,
  3. Jan Peter Kraus3

Published Online: 15 DEC 2010

DOI: 10.1002/9780470015902.a0005935.pub2



How to Cite

Kožich, V., Kruger, W. D. and Kraus, J. P. 2010. Cystathionine β-synthase (CBS) Deficiency: Genetics. eLS. .

Author Information

  1. 1

    Charles University in Prague, First Faculty of Medicine, Prague, Czech Republic

  2. 2

    Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

  3. 3

    University of Colorado School of Medicine, Aurora, Colorado, USA

Publication History

  1. Published Online: 15 DEC 2010


Cystathionine β-synthase (CBS) is an enzyme that catalyses condensation of homocysteine and serine to cystathionine. CBS deficiency, an autosomal recessive trait with estimated population frequency of around 1:10 000–1:20 000, resembles in the most severe forms Marfan syndrome with thromboembolism and neurological impairment, whereas milder forms may manifest with only thromboembolism or may remain asymptomatic. Laboratory findings include grossly elevated plasma total homocysteine and in part of patients also elevated blood methionine; the latter feature is utilised in neonatal screening. CBS binds three cofactors: pyridoxal 5′-phosphate, an allosteric activator S-adenosylmethionine and haem with as yet unresolved function. In the CBS gene, more than 150 different mutations have been described to date, almost 90% of them are missense variants. Although some of the mutations affect ribonucleic acid processing and its stability, the majority of mutations lead to enzyme misfolding and misassembly, which may be in part rescued by chemical or molecular chaperones.

Key Concepts:

  • Cystathionine β-synthase catalyses the first step in homocysteine trans-sulfuration.

  • Cystathionine β-synthase is a modular enzyme composed of a haem-binding N-terminal domain, the catalytically active core and the C-terminal autoinhibitory domain.

  • More than 150 different pathogenic mutations have been described in the CBS gene, almost 90% of all mutant CBS alleles carry missense mutations.

  • Misfolding and misassembly of mutant CBS subunits is a common pathogenic mechanism leading to CBS deficiency.

  • Mutation topology predicts in part the behaviour of mutant CBS enzymes, solvent accessible mutations have less severe effect than those buried in the enzyme globule.

  • Deficient CBS activity leads to gross elevation of plasma total homocysteine and often to elevated blood methionine levels.

  • Phenotypic consequences of mutations in the CBS gene include thromboembolism and vascular occlusion, which is accompanied in some patients by lens dislocation, marfanoid features and varying degree of neurological involvement.

  • Population frequency of clinically ascertained patients with CBS deficiency is one to two orders of magnitude lower than the frequency calculated from the prevalence of heterozygotes for pathogenic mutations; this observation indicates an ascertainment bias or lack of symptoms in many CBS-deficient individuals.

  • Murine models of CBS deficiency recapitulate in part the pathophysiology and organ involvement observed in human patients.


  • homocysteine;
  • homocystinuria;
  • inborn errors of metabolism;
  • cystathionine β-synthase;
  • mutations;
  • pathogenesis;
  • misfolding;
  • chaperones;
  • mouse models