Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1996 Dec;59(6):1262–1267.

High prevalence of a mutation in the cystathionine beta-synthase gene.

M Y Tsai 1, M Bignell 1, K Schwichtenberg 1, N Q Hanson 1
PMCID: PMC1914870  PMID: 8940271

Abstract

We found that a mutation previously described by Sebastio et al., involving a 68-bp insertion in the coding region of exon 8 of the cystathionine-beta-synthase (CBS) gene in a single patient with homocystinuria, is highly prevalent. In our control population, 11.7% (9/77) of the individuals were heterozygous carriers of this mutation. In contrast to the previous report, which assumed that the 68-bp insertion introduced a premature-termination codon and resulted in a nonfunctional CBS enzyme, we found that the presence of this mutation is not associated with hyperhomocysteinemia. Assay of CBS activity in transformed lymphocytes from individuals who were heterozygous or homozygous for this mutation showed normal activity. Furthermore, reverse-transcripion-PCR showed that individuals carrying this mutation have normal size mRNA. Our results suggest that the insertion creates an alternate splicing site, which eliminates not only the inserted intronic sequences but also the T833C mutation associated with this insertion. The net result is the generation of both quantitatively and qualitatively normal mRNA and CBS enzyme. Although the mutation does not seem to affect the activity of the CBS enzyme, the prevalence is somewhat increased in patients with premature coronary-artery disease, although the difference is not statistically significant.

Full text

PDF
1265

Images in this article

1264Figure 1
on p.1264

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson M. A., Gusella J. F. Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro. 1984 Nov;20(11):856–858. doi: 10.1007/BF02619631. [DOI] [PubMed] [Google Scholar]
  2. Boers G. H., Fowler B., Smals A. G., Trijbels F. J., Leermakers A. I., Kleijer W. J., Kloppenborg P. W. Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts. Hum Genet. 1985;69(2):164–169. doi: 10.1007/BF00293290. [DOI] [PubMed] [Google Scholar]
  3. Cheng J., Maquat L. E. Nonsense codons can reduce the abundance of nuclear mRNA without affecting the abundance of pre-mRNA or the half-life of cytoplasmic mRNA. Mol Cell Biol. 1993 Mar;13(3):1892–1902. doi: 10.1128/mcb.13.3.1892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clarke R., Daly L., Robinson K., Naughten E., Cahalane S., Fowler B., Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991 Apr 25;324(17):1149–1155. doi: 10.1056/NEJM199104253241701. [DOI] [PubMed] [Google Scholar]
  5. Engbersen A. M., Franken D. G., Boers G. H., Stevens E. M., Trijbels F. J., Blom H. J. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet. 1995 Jan;56(1):142–150. [PMC free article] [PubMed] [Google Scholar]
  6. Hu F. L., Gu Z., Kozich V., Kraus J. P., Ramesh V., Shih V. E. Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. Hum Mol Genet. 1993 Nov;2(11):1857–1860. doi: 10.1093/hmg/2.11.1857. [DOI] [PubMed] [Google Scholar]
  7. Kluijtmans L. A., Blom H. J., Boers G. H., van Oost B. A., Trijbels F. J., van den Heuvel L. P. Two novel missense mutations in the cystathionine beta-synthase gene in homocystinuric patients. Hum Genet. 1995 Aug;96(2):249–250. doi: 10.1007/BF00207394. [DOI] [PubMed] [Google Scholar]
  8. Kraus J. P. Komrower Lecture. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis. 1994;17(4):383–390. doi: 10.1007/BF00711354. [DOI] [PubMed] [Google Scholar]
  9. Lavigueur A., La Branche H., Kornblihtt A. R., Chabot B. A splicing enhancer in the human fibronectin alternate ED1 exon interacts with SR proteins and stimulates U2 snRNP binding. Genes Dev. 1993 Dec;7(12A):2405–2417. doi: 10.1101/gad.7.12a.2405. [DOI] [PubMed] [Google Scholar]
  10. Sebastio G., Sperandeo M. P., Panico M., de Franchis R., Kraus J. P., Andria G. The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations. Am J Hum Genet. 1995 Jun;56(6):1324–1333. [PMC free article] [PubMed] [Google Scholar]
  11. Selhub J., Jacques P. F., Bostom A. G., D'Agostino R. B., Wilson P. W., Belanger A. J., O'Leary D. H., Wolf P. A., Schaefer E. J., Rosenberg I. H. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995 Feb 2;332(5):286–291. doi: 10.1056/NEJM199502023320502. [DOI] [PubMed] [Google Scholar]
  12. Shih V. E., Fringer J. M., Mandell R., Kraus J. P., Berry G. T., Heidenreich R. A., Korson M. S., Levy H. L., Ramesh V. A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet. 1995 Jul;57(1):34–39. [PMC free article] [PubMed] [Google Scholar]
  13. Sperandeo M. P., Panico M., Pepe A., Candito M., de Franchis R., Kraus J. P., Andria G., Sebastio G. Molecular analysis of patients affected by homocystinuria due to cystathionine beta-synthase deficiency: report of a new mutation in exon 8 and a deletion in intron 11. J Inherit Metab Dis. 1995;18(2):211–214. doi: 10.1007/BF00711769. [DOI] [PubMed] [Google Scholar]
  14. Stampfer M. J., Malinow M. R., Willett W. C., Newcomer L. M., Upson B., Ullmann D., Tishler P. V., Hennekens C. H. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992 Aug 19;268(7):877–881. [PubMed] [Google Scholar]
  15. Tsai M. Y., Garg U., Key N. S., Hanson N. Q., Suh A., Schwichtenberg K. Molecular and biochemical approaches in the identification of heterozygotes for homocystinuria. Atherosclerosis. 1996 Apr 26;122(1):69–77. doi: 10.1016/0021-9150(95)05748-x. [DOI] [PubMed] [Google Scholar]
  16. Tsai M. Y., Hanson N. Q., Bignell M. K., Schwichtenberg K. A. Simultaneous detection and screening of T833C and G919A mutations of the cystathionine beta-synthase gene by single-strand conformational polymorphism. Clin Biochem. 1996 Oct;29(5):473–477. doi: 10.1016/0009-9120(96)00045-8. [DOI] [PubMed] [Google Scholar]
  17. Xu R., Teng J., Cooper T. A. The cardiac troponin T alternative exon contains a novel purine-rich positive splicing element. Mol Cell Biol. 1993 Jun;13(6):3660–3674. doi: 10.1128/mcb.13.6.3660. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES