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Functional assays testing pathogenicity of 14 cystathionine-beta synthase mutations
Open accessAbstract
In this study, 14 CBS alleles from homocystinuric patients were expressed heterologously in E. coli and their enzyme activities were assayed in vitro. Additionally, mutant CBS proteins were visualized by Western blot from denaturing and non-denaturing polyacrylamide gels. The 14 mutations characterized were: p.R125W (c.373C>T), p.G148R (c.442G>A), p.M173V (c.517A>G), p.T191M (c.572C>T), p.A226T (c.676G>A), p.C275Y (c.824G>A), p.R336C (c.1006C>T), p.R336H (c.1007G>A), p.L338P (c.1013T>C), p.S349N (c.1046G>A), p.R379Q (c.1136G>A), p.L456P (c.1367T>C), p.G522fsX540 (c.1566delG), and p.R548Q (c.1643G>A). Eleven of the mutant alleles exhibited an activity lower than 4% of the wild-type protein. In contrast, mutations p.A226T and p.M173V presented 20% and 40% of the wild-type activity, respectively, whereas the activity of p.R548Q was up to 60% of the wild-type. This suggests that it is a new rare variant rather than a pathogenic mutation. Most of the mutated proteins exhibited a decreased signal in Western blot analyses. The non-denaturing PAGE revealed that the wild-type protein retained the capacity to form a multimeric quaternary structure, whereas in the mutations p.M173V, p.A226T, and p.G548Q, this structure grade was dramatically reduced and was completely absent in the rest of the mutations.
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“However to date, the molecular explanation underlying phenotypic evidence in animal models 25,29 and phenotypegenotype correlations in TBS patients 47,60,32 remained unclear.”
From Tetramerisation governs SALL transcription factor function in development and disease (2025) · cites this paper as [60]
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Cites
Scott, J. W., Hawley, S. A., Green, K. A., Anis, M., Stewart, G., Scullion, G. A., Norman, D. G., & Hardie, D. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19874 · Cited by 754 · cited 1×
“This region is predicted to contain a pair of protein folding motifs called “CBS domains” [Bateman, 1997] that are hydrophobic and that are postulated to play a role as energy sensors [Scott et al., 2004].”
BackgroundThe structure of a domain common to archaebacteria and the homocystinuria disease protein.
Bateman, A. (1997) · TIBS -Trends in Biochemical Sciences. Regular ed · doi:10.1016/s0968-0004(96)30046-7 · Cited by 544 · cited 1×
“This region is predicted to contain a pair of protein folding motifs called “CBS domains” [Bateman, 1997] that are hydrophobic and that are postulated to play a role as energy sensors [Scott et al., 2004].”
BackgroundStructure of human cystathionine β‐synthase: a unique pyridoxal 5′‐phosphate‐dependent heme protein
Meier, M., Janošík, M., Kéry, V., Kraus, J., & Burkhard, P. (2001) · EMBO Journal · doi:10.1093/emboj/20.15.3910 · Cited by 301 · cited 2×
“This truncated protein has been crystallized [Meier et al., 2001; Taoka et al., 2002] and its structure is now well characterized [Meier et al., 2003; Banerjee and Zou, 2005].”
BackgroundBanerjee, R. V., & Zou, C.-G. (2004) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2004.08.037 · Cited by 226 · cited 1×
“This truncated protein has been crystallized [Meier et al., 2001; Taoka et al., 2002] and its structure is now well characterized [Meier et al., 2003; Banerjee and Zou, 2005].”
BackgroundTaoka, S., Lepore, B. W., Kabil, O., Ojha, S., Ringe, D., & Banerjee, R. (2002) · Biochemistry · doi:10.1021/bi026052d · Cited by 129 · cited 2×
“The first 70 residues of the N-terminal domain bind one heme molecule that plays a role in the redox sensitivity of CBS [Taoka et al., 2002].”
BackgroundBurkhard, P., Tai, C., Ristroph, C. M., Cook, P., & Jansonius, J. N. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3002 · Cited by 117
Shan, X., Dunbrack, R. L., Christopher, S., & Kruger, W. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.6.635 · Cited by 110
Kožich, V., & Kraus, J. (1992) · Human Mutation · doi:10.1002/humu.1380010206 · Cited by 109 · cited 2×
“All CBS mutant constructs were derived from the wild-type CBS expression plasmid pHCS3 [Kozich and Kraus, 1992], a gift from the authors of that study.”
MethodCorrection of disease-causing CBS mutations in yeast
Shan, X., & Kruger, W. (1998) · Nature Genetics · doi:10.1038/ng0598-91 · Cited by 96 · cited 1×
“African American [Shan and Kruger, 1998 & Kruger et al., 2003] Argentinian [Urreizti et al., submitted] c.824G>A p.C275Y Ex 7 + Bfu I Spanish [Urreizti et al., 2003] c.1006C>T p.R336C Ex 9 - Aci I English [de Franchis et al., 1999] Anglo-celtic [Gaustadnes et al., 2002] Spanish, Portuguese…”
Janošík, M., Oliveriusová, J., Janošíková, B., Sokolová, J., Kraus, E., Kraus, J., & Kožich, V. (2001) · American Journal of Human Genetics · doi:10.1086/320597 · Cited by 81 · cited 2×
“…Spanish [Urreizti et al., 2003] c.1643G>A p.R548Q Ex 16 - Bsr BI Spanish [Urreizti et al., unpublished] Protein analysis Western blot analysis of the soluble fraction of the crude cell lysates was performed under denaturing conditions as described [Janosik et al., 2001], with some modifications.”
BackgroundMethodPrevalence of congenital homocystinuria in Denmark.
Gaustadnes, M., Ingerslev, J., & Rütiger, N. (1999) · New England Journal of Medicine · doi:10.1056/nejm199905133401915 · Cited by 69 · cited 1×
“The estimated birth incidence of CBS deficiency ranges from 1:20,000 to 1:350,00 in different populations [Gaustadnes et al., 1999; Mudd et al., 2001].”
BackgroundKruger, W., Wang, L., Jhee, K., Singh, R., & Elsas, L. (2003) · Human Mutation · doi:10.1002/humu.10290 · Cited by 67 · cited 2×
“The activity found for this mutant in our assays (19.3%), is similar to that found by Kruger et al. [2003] in a yeast expression system (13%).”
ResultInfluentialOliveriusová, J., Kéry, V., Maclean, K., & Kraus, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207087200 · Cited by 62
Gaustadnes, M., Wilcken, B., Oliveriusová, J., McGill, J., Fletcher, J., Kraus, J., & Wilcken, D. (2002) · Human Mutation · doi:10.1002/humu.10104 · Cited by 62 · cited 1×
“…c.824G>A p.C275Y Ex 7 + Bfu I Spanish [Urreizti et al., 2003] c.1006C>T p.R336C Ex 9 - Aci I English [de Franchis et al., 1999] Anglo-celtic [Gaustadnes et al., 2002] Spanish, Portuguese [Urreizti et al., 2003] c.1007G>A p.R336H Ex 9 - Aci I North African [Coude et al, 1998] Moroccan…”
BackgroundInsertion of Alu element responsible for acute intermittent porphyria
Mustajoki, S., Ahola, H., Mustajoki, P., & Kauppinen, R. (1999) · Human Mutation · doi:10.1002/(sici)1098-1004(1999)13:6 · Cited by 38
Urreizti, R., Balcells, S., Rodés, M., Vilarinho, L., Baldellou, A., Couce, M. L., Muñoz, C., Campistol, J., Pintó, X., Vilaseca, M. A., et al. (2003) · Human Mutation · doi:10.1002/humu.9153 · Cited by 34 · cited 8×
“…2003] c.1367T>C p.L456P Ex 13 + Ava I Spanish [Urreizti et al., 2003] c.1566delG p.G522fsX540 Ex 16 - Nci I Portuguese [Castro et al, 1999] Spanish [Urreizti et al., 2003] c.1643G>A p.R548Q Ex 16 - Bsr BI Spanish [Urreizti et al., unpublished] Protein analysis Western blot analysis of the soluble…”
BackgroundInfluentialSelf-citationLucca, M. D., & Casique, L. (2004) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2003.12.003 · Cited by 20
Fatal haemorrhagic infarct in an infant with homocystinuria
Cardo, E., Campistol, J., Caritg, J., Ruiz, S., Vilaseca, M., Kirkham, F., & Blom, H. (1999) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.1999.tb00566.x · Cited by 18 · cited 1×
“Altogether, these data suggest that it is a rare variant rather than a pathogenic mutation, and that it is not responsible for the disease in this patient who presented with negligible CBS activity [Cardo et. al., 1999].”
BackgroundSelf-citationFour novel mutations at the cystathionine β-synthase locus causing homocystinuria
Coudé, M., Aupetit, J., Zabot, M., Kamoun, P., & Chadefaux-Vekemans, B. (1998) · Journal of Inherited Metabolic Disease · doi:10.1023/a:1005466601461 · Cited by 7 · cited 1×
“…et al., 1999] Anglo-celtic [Gaustadnes et al., 2002] Spanish, Portuguese [Urreizti et al., 2003] c.1007G>A p.R336H Ex 9 - Aci I North African [Coude et al, 1998] Moroccan [Urreizti et al., unpublished] c.1013T>C p.L338P Ex 9 + Pvu I Spanish [Urreizti et al., 2003] c.1046G>A p.S349N Ex 10 +…”
Research works printed but not linked: 3
- Kluijtmans L. A. J., Boers G. H. J., Kraus J. P., van den Heuvel L. P. W. J., Cruysberg J. R. M., Trijbels F. J. M. and Blom, H. J. (1998). The molecular basis of homocystinuria due to cystathionine ß-synthase deficiency in Dutch homocystinuria patients. Effect of CBS genotype on biochemical and clinical phenotype, and on response upon treatment. Ph.D. Thesis, University of Nijmegen, the Netherlands.
- Kraus JP. 1998. Biochemistry and molecular genetics of cystathionine beta-synthase deficiency. Eur J Pediatr 157 S2:S50-3. 10981004, 2006, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/humu.9395, Wiley Online Library on [01/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
- Mudd SH, H.L L, Kraus JP. 2001. Disorders of transsulfuration. In: Scriver CR, Beaudet, A.L., Sly, W.S, Valle, D., Childs, B., Kinzler, K.W. and Vogelstein, B., editor. The metabolic and Molecular bases of inherited disease. New York: McGraw-Hill. p 2007-2056.
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A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
Sun, S., Weile, J., Verby, M., Wu, Y., Wang, Y., Coté, A. G., Fotiadou, I., Kitaygorodsky, J., Vidal, M., Rine, J., et al. (2020) · Genome Medicine · doi:10.1186/s13073-020-0711-1 · Cited by 74
Surrogate Genetics and Metabolic Profiling for Characterization of Human Disease Alleles
Mayfield, J. A., Davies, M. W., Dimster-Denk, D., Pleskac, N., McCarthy, S., Boydston, E. A., Fink, L., Lin, X., Narain, A. S., Meighan, M., et al. (2012) · Genetics · doi:10.1534/genetics.111.137471 · Cited by 49
Homeostasis and Dynamic Stability of the Phenotype Link Robustness and Plasticity
Nijhout, H. F., & Reed, M. C. (2014) · Integrative and Comparative Biology · doi:10.1093/icb/icu010 · Cited by 45
“…and Lievers et al. (2001) MTHFR A1298C 68 B9 (folate) TS 2rpt/3rpt 42 B9 (folate) Trinh et al. (2002) and Kealey et al. (2005) TS 1494del6 24 CBS M173V 38 B6 (pyridoxal-P) Pogribna et al. (2001) and Urreizti et al. (2006) CBS A226T 19 CBS R548Q 60 CBS Down 150 *Activity of the homozygous mutant.”
Harrison, S. J., Nishinakamura, R., Jones, K. R., & Monaghan, A. P. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.002873 · Cited by 42
Mendes, M. I., Colaço, H. G., Smith, D. E. C., Ramos, R., Pop, A., Dooren, S. V., de Almeida, I. T., Kluijtmans, L., Janssen, M., Rivera, I., et al. (2014) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-013-9647-6 · Cited by 32
“Our results are in close agreement with those reported in the literature for the known mutations p.P49L (Cozar et al 2011; Kopecka et al 2011), p.I278T (Shan et al 2001), p.R336H (Urreizti et al 2006) and p.D444N (Evande et al 2002), thus validating our experimental model.”
BackgroundResult
Metadata
- Authors
- Urreizti, R., Asteggiano, C., Cozar, M., Frank, N., Vilaseca, M. A., Grinberg, D., & Balcells, S.
- Affiliations
- Universitat de Barcelona (ES)
- Corresponding author
- Balcells, Susana
- Venue
- Human Mutation
- Publisher
- Hindawi Limited
- Published
- 2006-02
- Volume
- 27
- Issue
- 2
- Pages
- 211-211
- ISSN
- 1059-7794 (ISSN-L)
- 1098-1004
- OpenAlex
- W1988357957
- Cited by
- 23
- References
- 23
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2022: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 2
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Universitat de Barcelona
- Fundación Carolina
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- cystathionine beta-synthase, homocystinuria, enzyme activity, pathogenicity, rare variants, quaternary structure, protein oligomerization, functional assays, heterologous expression
- MeSH terms
- Alleles, Amino Acid Sequence, Cystathionine beta-Synthase, DNA Mutational Analysis, Electrophoresis, Polyacrylamide Gel, Escherichia coli, Humans, Molecular Sequence Data, Mutation, Protein Conformation, Blotting, Western, Sequence Homology, Amino Acid, Mutation, Missense, Protein Structure, Quaternary
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