Cystathionine β‐Synthase (CBS) Deficiency: Genetics

Abstract

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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References

Akahoshi N, Kobayashi C, Ishizaki Y, et al. (2008) Genetic background conversion ameliorates semi‐lethality and permits behavioral analyses in cystathionine beta‐synthase‐deficient mice, an animal model for hyperhomocysteinemia. Human Molecular Genetics 17 (13): 1994–2005.

Anashkin VA, Baykov AA and Lahti R (2017) Enzymes regulated via cystathionine beta‐synthase domains. Biochemistry (Mosc) 82 (10): 1079–1087.

Banerjee R (2017) Catalytic promiscuity and heme‐dependent redox regulation of H2S synthesis. Current Opinion in Chemical Biology 37: 115–121.

Bruno S, Schiaretti F, Burkhard P, et al. (2001) Functional properties of the active core of human cystathionine beta‐synthase crystals. Journal of Biological Chemistry 276 (1): 16–19.

Bublil EM, Majtan T, Park I, et al. (2016) Enzyme replacement with PEGylated cystathionine beta‐synthase ameliorates homocystinuria in murine model. Journal of Clinical Investigation 126 (6): 2372–2384.

Carballal S, Madzelan P, Zinola CF, et al. (2008) Dioxygen reactivity and heme redox potential of truncated human cystathionine beta‐synthase. Biochemistry 47 (10): 3194–3201.

Carballal S, Cuevasanta E, Marmisolle I, et al. (2013) Kinetics of reversible reductive carbonylation of heme in human cystathionine beta‐synthase. Biochemistry 52 (26): 4553–4562.

Chen X, Wang L, Fazlieva R and Kruger WD (2006) Contrasting behaviors of mutant cystathionine beta‐synthase enzymes associated with pyridoxine response. Human Mutation 27 (5): 474–482.

Ereno‐Orbea J, Majtan T, Oyenarte I, Kraus JP and Martinez‐Cruz LA (2013a) Structural basis of regulation and oligomerization of human cystathionine beta‐synthase, the central enzyme of transsulfuration. Proceedings of the National Academy of Sciences of the United States of America 110 (40): E3790–E3799.

Ereno‐Orbea J, Oyenarte I and Martinez‐Cruz LA (2013b) CBS domains: ligand binding sites and conformational variability. Archives of Biochemistry and Biophysics 540 (1‐2): 70–81.

Ereno‐Orbea J, Majtan T, Oyenarte I, Kraus JP and Martinez‐Cruz LA (2014) Structural insight into the molecular mechanism of allosteric activation of human cystathionine beta‐synthase by S‐adenosylmethionine. Proceedings of the National Academy of Sciences of the United States of America 111 (37): E3845–E3852.

Gan‐Schreier H, Kebbewar M, Fang‐Hoffmann J, et al. (2010) Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. Journal of Pediatrics 156 (3): 427–432.

Gaustadnes M, Ingerslev J and Rutiger N (1999) Prevalence of congenital homocystinuria in Denmark. New England Journal of Medicine 340 (19): 1513.

Gaustadnes M, Rudiger N, Rasmussen K and Ingerslev J (2000) Familial thrombophilia associated with homozygosity for the cystathionine beta‐synthase 833T–>C mutation. Arteriosclerosis, Thrombosis, and Vascular Biology 20 (5): 1392–1395.

Ge Y, Matherly LH and Taub JW (2001) Transcriptional regulation of cell‐specific expression of the human cystathionine beta ‐synthase gene by differential binding of Sp1/Sp3 to the ‐1b promoter. Journal of Biological Chemistry 276 (47): 43570–43579.

Gupta S, Kuhnisch J, Mustafa A, et al. (2009) Mouse models of cystathionine beta‐synthase deficiency reveal significant threshold effects of hyperhomocysteinemia. FASEB Journal 23 (3): 883–893.

Gupta S and Kruger WD (2011) Cystathionine beta‐synthase deficiency causes fat loss in mice. PLoS One 6 (11): e27598.

Gupta S, Wang L, Anderl J, et al. (2013) Correction of cystathionine beta‐synthase deficiency in mice by treatment with proteasome inhibitors. Human Mutation 34 (8): 1085–1093.

Gupta S, Melnyk SB and Kruger WD (2014) Cystathionine beta‐synthase‐deficient mice thrive on a low‐methionine diet. FASEB Journal 28 (2): 781–790.

Gupta S, Wang L and Kruger WD (2017) The c.797 G>A (p.R266K) cystathionine beta‐synthase mutation causes homocystinuria by affecting protein stability. Human Mutation 38 (7): 863–869.

Hnizda A, Majtan T, Liu L, et al. (2012) Conformational properties of nine purified cystathionine beta‐synthase mutants. Biochemistry 51 (23): 4755–4763.

Huemer M, Kozich V, Rinaldo P, et al. (2015) Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines. Journal of Inherited Metabolic Disease 38 (6): 1007–1019.

Jacobs F, Van Craeyveld E, Muthuramu I, et al. (2011) Correction of endothelial dysfunction after selective homocysteine lowering gene therapy reduces arterial thrombogenicity but has no effect on atherogenesis. Journal of Molecular Medicine (Berlin, Germany) 89 (10): 1051–1058.

Janosik M, Kery V, Gaustadnes M, Maclean KN and Kraus JP (2001a) Regulation of human cystathionine beta‐synthase by S‐adenosyl‐L‐methionine: evidence for two catalytically active conformations involving an autoinhibitory domain in the C‐terminal region. Biochemistry 40 (35): 10625–10633.

Janosik M, Oliveriusova J, Janosikova B, et al. (2001b) Impaired heme binding and aggregation of mutant cystathionine beta‐synthase subunits in homocystinuria. American Journal of Human Genetics 68 (6): 1506–1513.

Janosik M, Sokolova J, Janosikova B, et al. (2009) Birth prevalence of homocystinuria in Central Europe: frequency and pathogenicity of mutation c.1105C>T (p.R369C) in the cystathionine beta‐synthase gene. Journal of Pediatrics 154 (3): 431–437.

Jhee KH, Niks D, McPhie P, Dunn MF and Miles EW (2001) The reaction of yeast cystathionine beta‐synthase is rate‐limited by the conversion of aminoacrylate to cystathionine. Biochemistry 40 (36): 10873–10880.

Jiang H, Stabler SP, Allen RH, Abman SH and Maclean KN (2014) Altered hepatic sulfur metabolism in cystathionine beta‐synthase‐deficient homocystinuria: regulatory role of taurine on competing cysteine oxidation pathways. FASEB Journal 28 (9): 4044–4054.

Kabil O, Weeks CL, Carballal S, et al. (2011) Reversible heme‐dependent regulation of human cystathionine beta‐synthase by a flavoprotein oxidoreductase. Biochemistry 50 (39): 8261–8263.

Kabil O, Yadav V and Banerjee R (2016) Heme‐dependent metabolite switching regulates H2S synthesis in response to endoplasmic reticulum (ER) stress. Journal of Biological Chemistry 291 (32): 16418–16423.

Kery V, Poneleit L and Kraus JP (1998) Trypsin cleavage of human cystathionine beta‐synthase into an evolutionarily conserved active core: structural and functional consequences. Archives of Biochemistry and Biophysics 355 (2): 222–232.

Kery V, Poneleit L, Meyer JD, Manning MC and Kraus JP (1999) Binding of pyridoxal 5′‐phosphate to the heme protein human cystathionine beta‐synthase. Biochemistry 38 (9): 2716–2724.

Kopecka J, Krijt J, Rakova K and Kozich V (2011) Restoring assembly and activity of cystathionine beta‐synthase mutants by ligands and chemical chaperones. Journal of Inherited Metabolic Disease 34 (1): 39–48.

Kozich V and Kraus JP (1992) Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta‐synthase deficiency. Human Mutation 1 (2): 113–123.

Kozich V, Sokolova J, Klatovska V, et al. (2010) Cystathionine beta‐synthase mutations: effect of mutation topology on folding and activity. Human Mutation 31 (7): 809–819.

Kožich V, Morris AAM and Blom HJ (2016) Disorders of sulfur amino acid metabolism. In: Saudubray J‐M, Baumgartner MR and Walter J (eds) Inborn Metabolic Diseases: Diagnosis and Treatment, pp. 309–320. Berlin/Heidelberg: Springer.

Kraus JP, Janosik M, Kozich V, et al. (1999) Cystathionine beta‐synthase mutations in homocystinuria. Human Mutation 13 (5): 362–375.

Krijt J, Kopecka J, Hnizda A, et al. (2011) Determination of cystathionine beta‐synthase activity in human plasma by LC‐MS/MS: potential use in diagnosis of CBS deficiency. Journal of Inherited Metabolic Disease 34 (1): 49–55.

Kruger WD and Gupta S (2016) The effect of dietary modulation of sulfur amino acids on cystathionine beta synthase‐deficient mice. Annals of the New York Academy of Sciences 1363: 80–90.

Kruger WD (2017) Cystathionine beta‐synthase deficiency: of mice and men. Molecular Genetics and Metabolism 121 (3): 199–205.

Lee HO, Wang L, Kuo YM, et al. (2017) Lack of global epigenetic methylation defects in CBS deficient mice. Journal of Inherited Metabolic Disease 40 (1): 113–120.

Maclean KN, Kraus E and Kraus JP (2004) The dominant role of Sp1 in regulating the cystathionine beta‐synthase ‐1a and ‐1b promoters facilitates potential tissue‐specific regulation by Kruppel‐like factors. Journal of Biological Chemistry 279 (10): 8558–8566.

Maclean KN, Sikora J, Kozich V, et al. (2010a) Cystathionine beta‐synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment. Molecular Genetics and Metabolism 101 (2‐3): 163–171.

Maclean KN, Sikora J, Kozich V, et al. (2010b) A novel transgenic mouse model of CBS‐deficient homocystinuria does not incur hepatic steatosis or fibrosis and exhibits a hypercoagulative phenotype that is ameliorated by betaine treatment. Molecular Genetics and Metabolism 101 (2‐3): 153–162.

Maclean KN, Jiang H, Aivazidis S, et al. (2017) Taurine treatment prevents derangement of the hepatic gamma‐glutamyl cycle and methylglyoxal metabolism in a mouse model of classical homocystinuria: regulatory crosstalk between thiol and sulfinic acid metabolism. FASEB Journal 32 (3): 1265–1280.

Magner M, Krupkova L, Honzik T, et al. (2011) Vascular presentation of cystathionine beta‐synthase deficiency in adulthood. Journal of Inherited Metabolic Disease 34 (1): 33–37.

Majors AK and Pyeritz RE (2000) A deficiency of cysteine impairs fibrillin‐1 deposition: implications for the pathogenesis of cystathionine beta‐synthase deficiency. Molecular Genetics and Metabolism 70 (4): 252–260.

Majtan T, Liu L, Carpenter JF and Kraus JP (2010) Rescue of cystathionine beta‐synthase (CBS) mutants with chemical chaperones: purification and characterization of eight CBS mutant enzymes. The Journal of Biological Chemistry 285 (21): 15866–15873.

Majtan T, Pey AL, Fernandez R, et al. (2014) Domain organization, catalysis and regulation of eukaryotic cystathionine beta‐synthases. PLoS One 9 (8): e105290.

Majtan T, Pey AL and Kraus JP (2016) Kinetic stability of cystathionine beta‐synthase can be modulated by structural analogs of S‐adenosylmethionine: potential approach to pharmacological chaperone therapy for homocystinuria. Biochimie 126: 6–13.

Majtan T, Hulkova H, Park I, et al. (2017) Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria. FASEB Journal 31 (12): 5495–5506.

Majtan T, Krijt J, Sokolova J, et al. (2018a) Biogenesis of hydrogen sulfide and thioethers by cystathionine beta‐synthase. Antioxidants & Redox Signaling 28 (4): 311–323.

Majtan T, Jones W, Krijt J, et al. (2018b) Enzyme replacement therapy ameliorates multiple symptoms of murine homocystinuria. Molecular Therapy 6 (3): 834–844.

Meier M, Janosik M, Kery V, Kraus JP and Burkhard P (2001) Structure of human cystathionine beta‐synthase: a unique pyridoxal 5′‐phosphate‐dependent heme protein. EMBO Journal 20 (15): 3910–3916.

Melenovska P, Kopecka J, Krijt J, et al. (2015) Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate. Journal of Inherited Metabolic Disease 38 (2): 287–294.

Miles EW and Kraus JP (2004) Cystathionine beta‐synthase: structure, function, regulation, and location of homocystinuria‐causing mutations. Journal of Biological Chemistry 279 (29): 29871–29874.

Moorthie S, Cameron L, Sagoo GS, Bonham JR and Burton H (2014) Systematic review and meta‐analysis to estimate the birth prevalence of five inherited metabolic diseases. Journal of Inherited Metabolic Disease 37 (6): 889–898.

Morris AA, Kozich V, Santra S, et al. (2017) Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency. Journal of Inherited Metabolic Disease 40 (1): 49–74.

Mudd SH, Skovby F, Levy HL, et al. (1985) The natural history of homocystinuria due to cystathionine beta‐synthase deficiency. American Journal of Human Genetics 37 (1): 1–31.

Mudd SH, Levy HL and Kraus JP (2001) Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn, pp. 2007–2056. New York: McGraw‐Hill.

Oliveriusova J, Kery V, Maclean KN and Kraus JP (2002) Deletion mutagenesis of human cystathionine beta‐synthase. Impact on activity, oligomeric status, and S‐adenosylmethionine regulation. Journal of Biological Chemistry 277 (50): 48386–48394.

Pey AL, Majtan T, Sanchez‐Ruiz JM and Kraus JP (2013) Human cystathionine beta‐synthase (CBS) contains two classes of binding sites for S‐adenosylmethionine (SAM): complex regulation of CBS activity and stability by SAM. The Biochemical Journal 449 (1): 109–121.

Ratnam S, Maclean KN, Jacobs RL, et al. (2002) Hormonal regulation of cystathionine beta‐synthase expression in liver. Journal of Biological Chemistry 277 (45): 42912–42918.

Refsum H, Fredriksen A, Meyer K, Ueland PM and Kase BF (2004) Birth prevalence of homocystinuria. Journal of Pediatrics 144 (6): 830–832.

Robert K, Maurin N, Vayssettes C, Siauve N and Janel N (2005a) Cystathionine beta synthase deficiency affects mouse endochondral ossification. The Anatomical Record. Part A, Discoveries in Molecular, Cellular, and Evolutionary Biology 282 (1): 1–7.

Robert K, Nehme J, Bourdon E, et al. (2005b) Cystathionine beta synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liver. Gastroenterology 128 (5): 1405–1415.

Selhub J and Miller JW (1992) The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S‐adenosylmethionine of the remethylation and transsulfuration of homocysteine. American Journal of Clinical Nutrition 55 (1): 131–138.

Shan X and Kruger WD (1998) Correction of disease‐causing CBS mutations in yeast. Nature Genetics 19 (1): 91–93.

Shan X, Dunbrack RL Jr, Christopher SA and Kruger WD (2001) Mutations in the regulatory domain of cystathionine beta synthase can functionally suppress patient‐derived mutations in cis. Human Molecular Genetics 10 (6): 635–643.

Singh LR, Chen X, Kozich V and Kruger WD (2007) Chemical chaperone rescue of mutant human cystathionine beta‐synthase. Molecular Genetics and Metabolism 91 (4): 335–342.

Singh LR and Kruger WD (2009) Functional rescue of mutant human cystathionine beta‐synthase by manipulation of Hsp26 and Hsp70 levels in Saccharomyces cerevisiae. Journal of Biological Chemistry 284 (7): 4238–4245.

Singh S, Madzelan P, Stasser J, et al. (2009a) Modulation of the heme electronic structure and cystathionine beta‐synthase activity by second coordination sphere ligands: the role of heme ligand switching in redox regulation. Journal of Inorganic Biochemistry 103 (5): 689–697.

Singh S, Padovani D, Leslie RA, Chiku T and Banerjee R (2009b) Relative contributions of cystathionine beta‐synthase and gamma‐cystathionase to H2S biogenesis via alternative trans‐sulfuration reactions. Journal of Biological Chemistry 284 (33): 22457–22466.

Singh LR, Gupta S, Honig NH, Kraus JP and Kruger WD (2010) Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70. PLoS Genetics 6 (1): e1000807.

Skovby F, Gaustadnes M and Mudd SH (2010) A revisit to the natural history of homocystinuria due to cystathionine beta‐synthase deficiency. Molecular Genetics and Metabolism 99 (1): 1–3.

Sorensen JT, Gaustadnes M, Stabler SP, et al. (2016) Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia. Molecular Genetics and Metabolism 117 (3): 344–350.

Szabo C (2018) A timeline of hydrogen sulfide (H2S) research: from environmental toxin to biological mediator. Biochemical Pharmacology 149: 5–19.

Vadon‐Le Goff S, Delaforge M, Boucher JL, et al. (2001) Coordination chemistry of the heme in cystathionine beta‐synthase: formation of iron(II)‐isonitrile complexes. Biochemical and Biophysical Research Communications 283 (2): 487–492.

Vozdek R, Hnizda A, Krijt J, Kostrouchova M and Kozich V (2012) Novel structural arrangement of nematode cystathionine beta‐synthases: characterization of Caenorhabditis elegans CBS‐1. The Biochemical Journal 443 (2): 535–547.

Vyletal P, Sokolova J, Cooper DN, et al. (2007) Diversity of cystathionine beta‐synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion. Human Mutation 28 (3): 255–264.

Wang L, Jhee KH, Hua X, et al. (2004) Modulation of cystathionine beta‐synthase level regulates total serum homocysteine in mice. Circulation Research 94 (10): 1318–1324.

Wang L, Chen X, Tang B, et al. (2005) Expression of mutant human cystathionine beta‐synthase rescues neonatal lethality but not homocystinuria in a mouse model. Human Molecular Genetics 14 (15): 2201–2208.

Watanabe M, Osada J, Aratani Y, et al. (1995) Mice deficient in cystathionine beta‐synthase: animal models for mild and severe homocyst(e)inemia. Proceedings of the National Academy of Sciences of the United States of America 92 (5): 1585–1589.

Yap S, Boers GH, Wilcken B, et al. (2001) Vascular outcome in patients with homocystinuria due to cystathionine beta‐synthase deficiency treated chronically: a multicenter observational study. Arteriosclerosis, Thrombosis, and Vascular Biology 21 (12): 2080–2085.

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.

Websites

CBS gene map http://cbs.lf1.cuni.cz/cbsdata/genome.htm

ExacBrowser – Cbs Gene http://exac.broadinstitute.org/gene/ENSG00000160200

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

GeneCards: CBS Gene http://www.genecards.org/cgi‐bin/carddisp.pl?gene=CBS

Homocystinuria due to cystathionine beta‐synthase deficiency; MIM number: 236200 OMIM: http://www.ncbi.nlm.nih.gov/omim/236200

Homocystinuria Network America https://hcunetworkamerica.org/

Homocystinuria Network Australia https://www.hcunetworkaustralia.org.au/

Krauslab Homepage–University of Colorado Health Sciences Center http://medschool.ucdenver.edu/krauslab

Map of all CBS mutations http://cbs.lf1.cuni.cz/index.php

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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. http://www.els.net [doi: 10.1002/9780470015902.a0005935.pub3]