LKB1, the human gene encoding a serine threonine kinase, was recently ident
ified as a susceptibility gene for Peutz-Jeghers syndrome (PJS), a disease
characterized by the constellation of intestinal hamartomata, oral mucocuta
neous hyperpigmentation, and an increased risk for gastrointestinal as well
as extraintestinal malignancies. To date, the majority of individuals with
PJS have been found to have genetic alterations in LKB1, most of which res
ult in protein truncation. Additionally, linkage analyses have suggested a
modicum of genetic heterogeneity, with the majority of PJS families showing
linkage to the LKB1 locus. In this study, we evaluated five kindreds with
greater than two affected family members, five PJS probands with only one o
ther affected family member, as well as 23 individuals with sporadic PJS fo
r mutations within the LKB1 gene. Conformation sensitive gel electrophoresi
s was utilized for the initial screen, followed by direct sequence analysis
for characterization. Long-range PCR was used for the detection of larger
genetic insertions or deletions. Mutation analysis revealed generic alterat
ions in LKB1 in two probands who had a family history of PJS. LKB1 mutation
s were detected in only four of the remaining 23 cases of sporadic PJS, The
se data suggest the presence of significant genetic heterogeneity for PJS a
nd the involvement of other loci in this syndrome. Hum Mutat 16:23-30, 2000
. (C) 2000 Wiley-Liss, Inc.