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 familialPeutz-Jeghers syndrome (PJS) with intestinal hamartomatous polyps and anelevated risk of various neoplasms. To investigate the prevalence of LKB1germline mutations in PJS more generally, we studied samples from 33unrelated PJS patients including eight non-familial sporadic patients, 20familial patients and five patients with unknown family history. Nineteengermline mutations were identified, 12 (60%) in familial and four (50%) insporadic cases. LKB1 mutations were not detected in 14 (42%) patients,indicating that the existence of additional minor PJS loci cannot beexcluded. LKB1 is predicted to encode a serine/threonine kinase. Todemonstrate the putative Lkb1 kinase function and to study the consequencesof LKB1 mutations in PJS and sporadic tumors, we have analyzed the kinaseactivity of wild-type and mutant Lkb1 proteins. Interestingly, while mostof the small deletions or missense mutations resulted in loss-of-functionalleles, one missense mutation (G163D) previously identified in a sporadictesticular tumor demonstrated severely impaired but detectable kinaseactivity.