Cystathionine β‐Synthase (CBS) Deficiency: Genetics


Cystathionine β‐synthase (CBS) catalyses condensation of homocysteine and serine to cystathionine, and by alternative reactions also synthesis of hydrogen sulfide. CBS deficiency, an autosomal recessive trait with estimated worldwide frequency of 0.82–1.09 per 100 000 births, manifests usually by thromboembolism, and in severe forms also by lens dislocation, marfanoid features, osteoporosis and neuropsychiatric complications. Laboratory findings include grossly elevated plasma total homocysteine and mildly to grossly elevated blood methionine, which is analysed 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 160 different mutations have been described to date. Most of the mutations are missense yielding misfolded enzymes, which can potentially be rescued by chaperones. CBS deficiency is efficiently treated by combination of large doses of pyridoxine, methionine‐restricted diet and betaine; experimental enzyme replacement therapy is efficient in mouse models of disease.

Key Concepts

  • Cystathionine β‐synthase catalyses the first step in the transsulfuration of homocysteine to cysteine, and also synthesis of hydrogen sulfide from cysteine.
  • Cystathionine β‐synthase is a modular enzyme composed of a haem‐binding N‐terminal domain, the active core with pyridoxal‐5′‐phosphate involved in catalysis and the C‐terminal autoinhibitory domain, which binds S‐adenosylmethionine.
  • More than 160 different pathogenic mutations have been described in the CBS gene, almost 90% of all mutant CBS alleles carry missense mutations.
  • Mutant CBS subunits often misfold, and their conformation and activity may be rescued by chaperones.
  • Deficient CBS activity leads to gross elevation of plasma total homocysteine, often to elevated blood methionine levels, and decreased blood cystathionine.
  • Phenotypic consequences of mutations in the Cbs gene include thromboembolism and vascular occlusion, which is accompanied in severe forms of the disease by lens dislocation, marfanoid features, osteoporosis and neuropsychiatric involvement.
  • CBS deficiency can be managed by administration of pyridoxine, low‐methionine diet and betaine; treatment is efficient when started early after birth.
  • Population frequency of patients with CBS deficiency ascertained clinically and by newborn screening 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.
  • Various murine models of CBS deficiency recapitulate the organ involvement observed in human patients, and experimental enzyme replacement therapy corrects efficiently these complications.

Keywords: homocysteine; homocystinuria; inborn errors of metabolism; cystathionine β‐synthase; mutations; pathogenesis; misfolding; chaperones; mouse models; newborn screening; enzyme replacement therapy

Figure 1. Metabolism of sulfur amino acids. The typical intake of the essential amino acid methionine in adults is 1–2 g day−1. Methionine is converted by methionine adenosyltransferases (MAT I/III and MATII) to S‐adenosylmethionine (SAM), which donates the methyl group in numerous biologically important methylation reactions; excess SAM is removed from the cycle by glycine N‐methyltransferase (GNMT). S‐adenosylhomocysteine (SAH) originating from transmethylations is cleaved by S‐adenosylhomocysteine hydrolase (SAHH) to homocysteine and adenosine. Homocysteine can be metabolised back to methionine by methionine synthase (MTR) with the help of methionine synthase reductase (MTRR) in the folate‐dependent remethylation pathway, or by the liver‐dependent betaine‐homocysteine methyltransferase (BHMT) using betaine as a methyl‐group donor. Alternatively, homocysteine can be irreversibly metabolised to sulfate by the transsulfuration pathway. Homocysteine is condensed with serine to form cystathionine, which is subsequently cleaved to form cysteine and α‐ketobutyrate; these reactions are catalysed by cystathionine β‐synthase (CBS) and cystathionine γ‐lyase (CTH), respectively. These two enzymes can also use cysteine and/or homocysteine to synthesise hydrogen sulfide. Cysteine can be further converted in a series of reactions into taurine. Mitochondrial oxidation of hydrogen sulfide and cysteine involves several steps yielding thiosulfate, sulfite and finally sulfate.
Figure 2. Domain organisation and structure of humanCBS. (a) The CBS polypeptide consists of three functional domains. The N‐terminal domain binds the haem cofactor via C52 and H65 as axial ligands. The central catalytic domain binds the PLP cofactor via Schiff bond with the ε‐amino group of K119. The C‐terminal regulatory domain includes a tandem of CBS domains (CBS1 and CBS2), where the CBS allosteric activator AdoMet binds. (b) Crystal structures of a dimeric full‐length CBS lacking the flexible loop 516–525 from CBS2 domain in a basal and activated conformations. In the basal conformation, regulatory domain from one subunit (blue) interacts with the catalytic core of the other subunit (orange) and thus exerts its autoinhibitory effect on the enzyme's catalytic activity. Binding of AdoMet leads to a conformational change and formation of a compact, disc‐shaped CBS module accompanied by kinetic stabilisation of the regulatory domain and activation of the catalytic core, thus yielding AdoMet‐bound activated conformation. The cofactors (haem, PLP and AdoMet) are shown as balls.
Figure 3. Ethnic distribution and variability of mutantCBSalleles. An updated database of mutations in the CBS gene is maintained at the Krauslab homepage (see ‘Websites’). The proportion and ethnic origin of 924 independent alleles were taken from this source.
Figure 4. Misfolding ofCBSmutants and correction by chaperones. (a) The series of 27 CBS mutants was expressed in E. coli, and the presence of antigen was assessed by SDS gel and western blotting, the quaternary structure was analysed by electrophoresis under nondenaturing conditions and western blotting. CBS antigen is present in all bacterial extracts confirming that the enzymes are expressed; however, a large proportion of mutants is misfolded as indicated by the lack of tetramers. (b) The same series of 27 mutants was expressed in the presence of haem precursor δ‐aminolevulinate, and of chemical chaperones glycerol and betaine. The pie chart indicates the proportion of mutants with rescued folding and/or activity (determined as increase of amounts of tetramer or activity more than 30%, respectively). (c) Seven selected mutants with measurable amounts of tetramers and activity were expressed in mammalian CHO‐K1 cells in the presence of haem arginate, aminooxyacetic acid (AOAA, an inhibitor of CBS) and phenylbutyrate (PBA, inducer of molecular chaperones). The pie chart shows the proportion of mutants with rescued folding and/or activity (determined as increase of amounts of tetramer or activity more than 30% in comparison to the effect on the wild‐type enzyme).
Figure 5. Efficacy ofERTin mouse models ofHCU. (a) Plasma concentrations of total homocysteine, cystathionine, total cysteine and methionine in ∼5‐month‐old negative controls (CBS HETERO, blue bars) and positive controls (CBS KO, red bars) compared to age‐matched CBS KO mice injected from birth with ERT (CBS KO + ERT, green bars; 3× a week, SC, 7.5 mg kg−1). (b) Effect of ERT on liver histopathology of CBS KO mouse at the light microscopy level (40× magnification). Findings in ∼3‐week‐old healthy CBS heterozygous mouse, which served as negative controls (CBS HETERO), were compared to age‐matched untreated homocystinuric mouse (CBS KO) and ERT‐treated CBS KO mouse (CBS KO + ERT; 3× a week, SC, 7.5 mg kg−1). Pictures show haematoxylin & eosin stained liver parenchyma, while insets illustrate Oil Red O specific stain of apolar lipids in the cytoplasm of hepatocytes. Yellow arrows point to focal hepatocellular necroses with resorptive inflammatory reaction. Orange and red arrows designate micro‐ and macrovesicular steatosis, respectively. Blue arrows denote enlarged hyperchromatic nuclei and prominent nucleoli. (c) Effect of ERT on facial alopecia in Tg‐I278T mouse. Headshots of untreated healthy CBS heterozygous mouse at 34 weeks of age (CBS HETERO) were compared to age‐matched untreated homocystinuric mouse (Tg‐I278T) and ERT‐treated Tg‐I278T mouse (Tg‐I278T + ERT; 3× a week, SC, 7.5 mg kg−1). (d) A portion of the lens and adjacent eye wall imaged from the posterior aspect by confocal microscopy. In negative control (CBS HETERO), zonular fibres (red) extended from the wall of the eye (white arrow) to attachment points near the lens equator (yellow arrow). Fibres then run for a few hundred micrometres across the lens surface towards the posterior pole. In untreated I278T mouse (Tg‐I278T), zonular immunofluorescence was generally reduced, fibre density decreased and fibres were absent from the posterior lens surface (orange arrow). In some regions, groups of fibres were broken and completely missing (red arrow). In ERT‐treated mouse (Tg‐I278T + ERT), staining intensity was largely restored, fibre integrity preserved and fibres were present on the posterior lens surface.


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Further reading

Carmel R and Jacobsen DW (2001) Homocysteine in health and disease, pp. 510. Cambridge, UK ; New York, Cambridge University Press.

Kabe Y, Yamamoto T, Kajimura M, et al. (2016) Cystathionine β‐synthase and PGRMC1 as CO sensors. Free Radic Biol Med. 99: 333–344.

Kožich V, Krijt J, Sokolová J, et al. (2016) Thioethers as markers of hydrogen sulfide production in homocystinurias. Biochimie 126: 14–20.

Kraus JP, Oliveriusova J, Sokolva J, et al. (1998) The human cystathionine beta‐synthase (CBS) gene: Complete sequence, alternative splicing, and polymorphisms. Genomics 52 (3): 312–324.

Mudd SH (2011) Hypermethioninemias of genetic and non‐genetic origin: A review. Am J Med Genet C Semin Med Genet. 157C (1): 3–32.

Phillips CM, Zatarain JR, Nicholls ME, et al. (2017) Upregulation of Cystathionine‐β‐Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis. Cancer Res. 77 (21): 5741–5754.

Refsum H, Smith AD, Ueland PM, et al. (2004) Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem. 50 (1): 3–32.

Stabler SP, Korson M, Jethva R, et al. (2013) Metabolic profiling of total homocysteine and related compounds in hyperhomocysteinemia: utility and limitations in diagnosing the cause of puzzling thrombophilia in a family. JIMD Rep. 11: 149–163.


CBS gene map

ExacBrowser – Cbs Gene

European Network and Registry for Homocystinurias and Methylation Defects http://www.e‐

GeneCards: CBS Gene‐bin/

Homocystinuria due to cystathionine beta‐synthase deficiency; MIM number: 236200 OMIM:

Homocystinuria Network America

Homocystinuria Network Australia

Krauslab Homepage–University of Colorado Health Sciences Center

Map of all CBS mutations

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Kožich, Viktor, Kraus, Jan P, and Majtan, Tomas(May 2018) Cystathionine β‐Synthase (CBS) Deficiency: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005935.pub3]