PEUTZ-JEGHERS-SYNDROME IS CAUSED BY MUTATIONS IN A NOVEL SERINE THREONINE KINASE

Peutz-Jeghers (PJ) syndrome is an autosomal-dominant disorder characte rized by melanocytic macules of the lips, multiple gastrointestinal ha martomatous polyps and an increased risk for various neoplasms, includ ing gastrointestinal cancer. The PJ gene was recently mapped to chromo some 19p13.3 by linkage analysis, with the highest lod score at marker D19S886. In a distance of 190 kb proximal to D19S886, we identified a nd characterized a novel human gene encoding the serine threonine kina se STK11. In a three-generation PJ family, we found an STK11 allele wi th a deletion of exons 4 and 5 and an inversion of exons 6 and 7 segre gating with the disease. Sequence analysis of STK11 exons in four unre lated PJ patients has identified three nonsense and one acceptor splic e site mutations. All five germline mutations are predicted to disrupt the function of the kinase domain, We conclude that germline mutation s in STK11, probably in conjunction with acquired genetic defects of t he second allele in somatic cells, cause the manifestations of PJ synd rome.