Nature Genetics
18, 38 - 43 (1998)
doi:10.1038/ng0198-38
Peutz-Jeghers syndrome is caused by mutations in a novel serine
threoninekinaseDieter E. Jenne1, 9, Heike Reomann1, Jun-ichi Nezu2, Waltraut Friedel3, Steffan Loff.4, Reinhard Jeschke5, Oliver Müller6, Walter Back7
& Michael Zimmer8
1,
9Department of Neuroimmunology, Max-Planck-Institute of Psychiatry, Am Klopferspitz ISA, 82152 Martinsried, Germany.
2Chugai Research Institute for Molecular Medicine, 153-2 Nagai Niihari Ibaraki 300-41, Japan.
3Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, 53111 Bonn, Germany.
4Department of Pediatric Surgery, Mannheim Clinics, University of Heidelberg, Theodor-Kutzer-Ufer, 68135 Mannheim, Germany.
5Children's Clinic and Polyclinic, University of Würzburg, losef-Schneider-Strasse 2, 97080 Würzburg, Germany.
6Department of Structural Biology, Max-Planck-Institute of Molecular Physiology, 44139 Dortmund, Germany.
7Department of Pathology, Mannheim Clinics, University of Heidelberg, Theodor-Kutzer Ufer, 68135 Mannheim, Germany.
8Institute of Clinical Biochemistry and Pathobiochemistry, University ofWürzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.
9e-mail:djenne@alf.biochem.mpg.de 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.
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