Skip to main content
SpringerLink
Log in

Novel sequence variants of the genes associated with the multiple endocrine neoplasia syndromes 1 and 2. Analysis by an “in silico approach”

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

MEN syndromes (1 and 2) are hereditary tumor syndromes inherited as autosomal dominant traits. The genes that harbor the mutations responsible for the development of these syndromes have been cloned in recent years. In the present study we applied an “in silico” approach to find previously undescribed sequence variants of the RET protooncogene and the MEN1 gene. Sequence comparisons were performed at the National Center for Biotechnology Information Database by the search tool blastn. We found several sequence alterations in both coding and noncoding sequences. The majority of polymorphisms described to date were found by our approach, in addition we observed novel sequence variants of both genes as well. These sequence variants may have both diagnostic and theoretical relevance. In silico strategies may represent new, and potentially effective ways for finding novel sequence variants.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sizemore G.W. Multiple endocrine neoplasia. In: Becker K.I. (Ed.) Principles of endocrinology and metabolism. J.B. Lippincott Company, Philadelphia, 1995, p. 1555–1563.

    Google Scholar 

  2. Skogseid E., Eriksson B., Lundqvist G. et al. Multiple endocrine neoplasia type 1: a 10-year prospective screening study in four kindreds. J. Clin. Endocrinol. Metab. 1991, 73: 281–287.

    Article  PubMed  CAS  Google Scholar 

  3. Chandrasekharappa S.C., Guru S.C., Manickam P. et al. Positional cloning of the gene for multiple endocrine neoplasiatype 1. Science 1997, 276: 404–406.

    Article  PubMed  CAS  Google Scholar 

  4. Mulligan L.M., Kwok J.B., Healey C.S. et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993, 363: 458–460.

    Article  PubMed  CAS  Google Scholar 

  5. Gagel R.F., Cote, G. The Ret signaling system and its role in hereditary medullary thyroid carcinoma. In: Econs M.J. (Ed.) The genetics of osteoporosis and metabolic bone disease. Humana Press Inc., Totowa, 2001, p. 295–308.

    Google Scholar 

  6. Edery P., Lyonnet S., Mulligan L.M. et al. Mutations of the RET proto-oncogene in Hirschprung’s disease. Nature 1994, 367: 378–380.

    Article  PubMed  CAS  Google Scholar 

  7. Libroia, A., Verga, U., Vecchi, G. et al. Seventeen-yearlong- follow-up of a family affected by type 2A multiple endocrine neoplasia (MEN2A). J Endocrinol Invest 1998, 21: 87–92.

    Article  PubMed  CAS  Google Scholar 

  8. Capes-Davis A., Robinson B.G. Return of the native: deducing the normal function of the RET proto-oncogene. Curr. Opin. Endocrinol. Diab. 1999, 6: 61–69.

    Article  CAS  Google Scholar 

  9. Eng C., Clayton D., Schuffenecker I. et al. The relationship between specific RET proto-oncogene mutations and disease genotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996, 276: 1575–1579.

    Article  PubMed  CAS  Google Scholar 

  10. Pacini F., Elisei R., Romei C., Pinchera A. RET proto-oncogene mutation in thyroid carcinomas: clinical relevance. J. Endocrinol. Invest. 2000, 23: 328–338.

    Article  PubMed  CAS  Google Scholar 

  11. Borrego S., Sáez M.E., Ruiz A. et al. Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschprung disease and may represent loci modifying phenotypic expression. J. Med. Genet. 1999, 36: 771–774.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Agarwal S.K., Kester M.B., Debelenko L.V. et al. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 1997, 6: 1169–1175.

    Article  PubMed  CAS  Google Scholar 

  13. Zhuang Z., Vortmeyer A.O., Pack S. et al. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res. 1997, 57: 4682–4686.

    PubMed  CAS  Google Scholar 

  14. Heppner C., Kester M.B., Agarwal S.K. et al. Somatic mutation of the MEN1 gene in parathyroid tumours. Nature Gen. 1997, 16: 375–378.

    Article  CAS  Google Scholar 

  15. Shan L., Nakamura Y., Nakamura M. et al. Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Lab. Invest. 1998, 78: 471–475.

    PubMed  CAS  Google Scholar 

  16. Igaz P., Fitzimons C.P., Szalai C., Falus A. In silico histamine genomics: polymorphisms (sequence variants) of the genes associated with the synthesis, action and metabolism of histamine. Am. J. Pharmacogenomics, in press.

  17. Useche F.J., Gao G. High-throughput identification, database storage and analyis of SNPs in EST sequences. Genome Inform. Ser. Workshop Genome Inform. 2001, 12: 194–203.

    CAS  Google Scholar 

  18. Altschul S.F., Madden T.L., Schäffer A.A. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997, 25: 3389–402.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Patrone G., Puliti A., Bocciardi R., Ravazzolo R., Romeo G. Sequence and characterization of the RET protooncogene 5′ flanking region: analysis of retinoic acid responsiveness at the transcriptional level. FEBS Lett 1997, 419: 76–82.

    Article  PubMed  CAS  Google Scholar 

  20. Munnes M., Patrone G., Schmitz B., Romeo G., Doerfler W. A 5′-CG-3′-rich region in the promoter of the transcriptionally frequently silenced RET protooncogene lacks methylated cytidine residues. Oncogene 1998, 17: 2573–2583.

    Article  PubMed  CAS  Google Scholar 

  21. Karges, W., Jostarndt, K., Maier, S. et al. Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region. J. Endocrinol. 2000, 166: 1–9.

    Article  PubMed  CAS  Google Scholar 

  22. Grieco M., Santoro M., Berlingieri M.T. et al. PTC is a novel rearranged form of the RET proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990, 60: 557–563, 1990.

    Article  PubMed  CAS  Google Scholar 

  23. Takahashi M., Cooper G.M. Ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol. Cell. Biol. 1987, 7: 1378–1385.

    PubMed Central  PubMed  CAS  Google Scholar 

  24. Takahashi M., Buma Y., Iwamoto T., Inaguma Y., Ikeda H., Hiai H. Cloning and expression of the RET-protooncogene encoding a tyrosine kinase with potential transmembrane domains. Oncogene 1988, 3: 571–578.

    PubMed  CAS  Google Scholar 

  25. Bongarzone I., Monzini N., Borrello M.G. et al. Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of RET tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A. Mol. Cell. Biol. 1993, 13: 358–366.

    PubMed Central  PubMed  CAS  Google Scholar 

  26. Munnes M., Fanaei S., Schmitz B., Muiznieks I., Holschneider A.M., Doerfler W. Familial form of Hirschprung disease: nucleotide sequence studies reveal point mutation in the RET proto-oncogene in two of six families but not in other candidate genes. Am. J. Med. Genet. 2000, 94: 19–27.

    Article  PubMed  CAS  Google Scholar 

  27. Gimm O., Neuberg D.S., Marsh D.J. et al. Over-representation of germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene 1999, 18: 1369–1370.

    Article  PubMed  CAS  Google Scholar 

  28. Fitze G., Schreiber M., Kuhlisch E., Schackert H.K., Roesner D. Association of RET protooncogene codon 45 polymorphism with Hirschprung disease. Am. J. Med. Genet. 1999, 65: 1469–1473.

    CAS  Google Scholar 

  29. Borrego S., Ruiz A., Sáez M.E. et al. RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschprung disease. J. Med. Genet. 2000, 37: 572–578.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Kedra D., Seroussi E., Fransson I. et al. The germinal center kinase gene and a novel CDC25-like gene are located in the vicinity of the PYGM gene on 11q13. Hum. Genet. 1997, 100: 611–619.

    Article  PubMed  CAS  Google Scholar 

  31. Evans C.O., Brown M.R., Parks J.S., Oyesiku N.M. Screening for MEN1 suppressor gene mutations in sporadic pituitary tumors. J. Endocrinol. Invest. 2000, 23: 304–309.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, 1088 Budapest, Szentkirályi str. 46, Budapest, Hungary

    P. Igaz, A. Patócs &  K. Rácz

Authors
  1. P. Igaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Patócs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Rácz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. Rácz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Igaz, P., Patócs, A. & Rácz, K. Novel sequence variants of the genes associated with the multiple endocrine neoplasia syndromes 1 and 2. Analysis by an “in silico approach”. J Endocrinol Invest 25, 609–613 (2002). https://doi.org/10.1007/BF03345084

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03345084

Key-words

Search

Navigation