Peutz-Jeghers syndrome is caused by mutations in a novel serine threoninekinase (original) (raw)

Nature Genetics volume 18, pages 38–43 (1998)Cite this article

Abstract

Peutz-Jeghers (PJ) syndrome is an autosomal-dominant disorder characterized by melanocytic macules of the lips, multiple gastrointestinal hamartomatous polyps and an increased risk for various neoplasms, including gastrointestinal cancer. The PJ gene was recently mapped to chromosome 19p13.3 by linkage analysis, with the highest lod score at marker D195886. In a distance of 190 kb proximal to D195886, we identified and characterized a novel human gene encoding the serine threonine kinase STK11. In a three-generation PJ family, we found an 5TK11 allele with a deletion of exons 4 and 5 and an inversion of exons 6 and 7 segregating with the disease. Sequence analysis of STK11 exons in four unrelated PJ patients has identified three nonsense and one acceptor splice site mutations. All five germline mutations are predicted to disrupt the function of the kinase domain. We conclude that germline mutations in STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells, cause the manifestations of PJ syndrome.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Giardiello, P.M. et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N. Engl.J.Med. 316, 1511–1514 (1987)
    Article CAS Google Scholar
  2. Spigelman, A.D ., Murday, V. & Phillips, R.K. Cancer and the Peutz-Jeghers syndrome. Gut 30, 1588–1590 (1989).
    Article Google Scholar
  3. Hemminki, A . et al. Localization of a susceptibilty locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nature Genet. 15, 87–90 (1997).
    Article CAS Google Scholar
  4. Amos, C.I. et al. Fine mapping of a genetic locus for Peutz-Jeghers syndrome on chromosome 19p. Cancer Res. 57, 3653–3656 (1997)
    Google Scholar
  5. Ashworth,, L.K. et al. An integrated metric physical map of human chromosome 19. Nature Genet. 11, 422–427(1995)
    Article CAS Google Scholar
  6. Schuler, G.D. et al. A gene map of the human genome. Science 274, 540–546 (1996)
    Article Google Scholar
  7. Hall, S.L. & Padgett, R.A. Conserved sequences in a class of rare eukaryotic nuclear introns with non-consensus splice sites. J. Mol. Biol. 239, 357–365 (1994)
    Article CAS Google Scholar
  8. Su, J.Y., Erikson, E. & Mailer, J.L Cloning and characterization of a novel serine/threonine protein kinase expressed in early Xenopus embryos. J. Biol. Chem. 271, 14430–14437 (1996).
    Article CAS Google Scholar
  9. Hanks, S.K. & Hunter, T Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576–596 (1995).
    Article CAS Google Scholar
  10. Steck, P.A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet. 15, 356–362(1997).
    Article CAS Google Scholar
  11. Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet. 16, 64–67 (1997).
    Article CAS Google Scholar
  12. Nishisho, I. et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665–669 (1991).
    Article CAS Google Scholar
  13. Joslyn, G. et al. Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 66, 601–613 (1991)
    Article CAS Google Scholar
  14. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997)
    Article CAS Google Scholar
  15. Kinzler, K.W. et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251, 1366–1370 (1991).
    Article CAS Google Scholar
  16. Zimmer, M. et al. Three human elastase-like genes coordinately expressed in the myelomonocyte lineage are organized as a single genetic locus on 19pter. Proc. Natl. Acad. Sci. USA 89, 8215–8219 (1992).
    Article CAS Google Scholar
  17. Pilat, D. et al. The human Met-ase gene (GZMM): structure, sequence, and close physical linkage to the serine protease gene cluster on 19p13. Genomics 24, 445–450 (1994).
    Article CAS Google Scholar
  18. Rackwitz, H.R., et al. Analysis of cosmids using linearization by phage lambda terminase. Gene 40, 259–266 (1985).
    Article CAS Google Scholar
  19. Loff, S. et al. Peutz-Jeghers syndrome: cases at the Mannheim clinic over 25 years. Langenbecks Arch. Chir. 380, 43–52 (1995).
    Article CAS Google Scholar

Download references

Author information

Authors and Affiliations

  1. 9Department of Neuroimmunology, Max-Planck-Institute of Psychiatry, Am Klopferspitz ISA, 82152, Martinsried, Germany
    Dieter E. Jenne & Heike Reomann
  2. Chugai Research Institute for Molecular Medicine, 153-2, Nagai Niihari Ibaraki, 300-41, Japan
    Jun-ichi Nezu
  3. Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, 53111, Bonn, Germany
    Waltraut Friedel
  4. Department of Pediatric Surgery, Mannheim Clinics, University of Heidelberg, Theodor-Kutzer-Ufer, 68135, Mannheim, Germany
    Steffan Loff.
  5. Children's Clinic and Polyclinic, University of Würzburg, losef-Schneider-Strasse 2, 97080, Würzburg, Germany
    Reinhard Jeschke
  6. Department of Structural Biology, Max-Planck-Institute of Molecular Physiology, 44139, Dortmund, Germany
    Oliver Müller
  7. Department of Pathology, Mannheim Clinics, University of Heidelberg, Theodor-Kutzer Ufer, 68135, Mannheim, Germany
    Walter Back
  8. Institute of Clinical Biochemistry and Pathobiochemistry, University ofWürzburg, Versbacher Strasse 5, 97078, Würzburg, Germany
    Michael Zimmer

Authors

  1. Dieter E. Jenne
    You can also search for this author inPubMed Google Scholar
  2. Heike Reomann
    You can also search for this author inPubMed Google Scholar
  3. Jun-ichi Nezu
    You can also search for this author inPubMed Google Scholar
  4. Waltraut Friedel
    You can also search for this author inPubMed Google Scholar
  5. Steffan Loff.
    You can also search for this author inPubMed Google Scholar
  6. Reinhard Jeschke
    You can also search for this author inPubMed Google Scholar
  7. Oliver Müller
    You can also search for this author inPubMed Google Scholar
  8. Walter Back
    You can also search for this author inPubMed Google Scholar
  9. Michael Zimmer
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Jenne, D., Reomann, H., Nezu, Ji. et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threoninekinase.Nat Genet 18, 38–43 (1998). https://doi.org/10.1038/ng0198-38

Download citation