Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease characterized by mucocutaneous pigmentation and hamartomatous polyps. There is an increa sed risk of benign and malignant tumors in the gastrointestinal tract and i n extraintestinal tissues. One PJS locus has been mapped to chromosome 19p1 3.33 a second locus is suspected on chromosome 19q13.4 in a minority of fam ilies. The PJS gene on 19p13.3 has recently been cloned, and it encodes the serine/threonine kinase LKB1. The gene, which is ubiquitously expressed, i s composed of 10 exons spanning 23 kb. Several LKB1 mutations have been rep orted in heterozygosity in PJS patients. In this study, we screened for LKB 1 mutations in nine PJS families of American, Spanish, Portuguese, French, Turkish, and Indian origin and detected seven novel mutations. These includ ed two frameshift mutations, one four-amino-acid deletion, two amino-acid s ubstitutions, and two splicing errors. Expression of mutant LKB1 proteins ( K78I, D17GN, W308C, and L67P) and assessment of their autophosphorylation a ctivity revealed a loss of the kinase activity in all of these mutants. The se results provide direct evidence that the elimination of the kinase activ ity of LKB1 is probably responsible for the development of the PJS phenotyp es. In two Indian families, we failed to detect any LKB1 mutation; in one o f these families, we previously had detected linkage to markers on 19q13.3- 4, which suggests locus heterogeneity of PJS. The elucidation of the molecu lar etiology of PJS and the positional cloning of the second potential PJS gene will further elucidate the involvement of kinases/phosphatases in the development of cancer-psedisposing syndromes.