Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer

Germline mutations in LKB1 have been reported to underlie familial Peutz-Je ghers syndrome (PJS) with intestinal hamartomatous polyps and an elevated r isk of various neoplasms. To investigate the prevalence of LKB1 germline mu tations in PJS more generally, we studied samples from 33 unrelated PJS pat ients including eight non-familial sporadic patients, 20 familial patients and five patients with unknown family history. Nineteen germline mutations were identified, 12 (60%) in familial and four (50%) in sporadic cases. LKB 1 mutations were not detected in 14 (42%) patients, indicating that the exi stence of additional minor PJS loci cannot be excluded. LKB1 is predicted t o encode a serine/threonine kinase, To demonstrate the putative Lkb1 kinase function and to study the consequences of LKB1 mutations in PJS and sporad ic tumors, we have analyzed the kinase activity of wild-type and mutant Lkb 1 proteins. Interestingly, while most of the small deletions or missense mu tations resulted in loss-of-function alleles, one missense mutation (G163D) previously identified in a sporadic testicular tumor demonstrated severely impaired but detectable kinase activity.