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Gastrointestinal Hamartomatous Polyposis in Lkb1 Heterozygous Knockout Mice¹

Institute of Experimental Animal Sciences, Osaka University Medical School, Osaka 565-0871, Japan [H. M.]; Banyu Tsukuba Research Institute, Tsukuba 300-2611, Japan [H. M.]; Departments of Pharmacology [M. N., T. I., M. O., M. M. T.] and Surgery [M. N.], Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; and Rowe Program in Genetics, Department of Biological Chemistry, University of California, Davis, California 95616 [M. F. S.]

Peutz-Jeghers syndrome (PJS) is a hereditary disorder characterized bygastrointestinal hamartomatous polyposis associated with mucocutaneous pigmentation. Germ-line mutations of the gene encoding LKB1 (STK11), a serine/threonine kinase, are identified in most PJS patients. To investigate the role of LKB1 in the PJS phenotypes, we introduced a germ-line mutation in the mouse Lkb1 gene by homologous recombination in mouse embryonic stem cells. In most Lkb1 (+/-) mice >20 weeks of age, hamartomatous polyps developed in the glandular stomach, often in the pyloric region. Small intestinal hamartomas also developed in approximately one-third of the Lkb1 (+/-) mice >50 weeks of age. A genomic PCR and sequence analysis showed that all hamartomas retained both the wild-type and targeted Lkb1 alleles, indicating that allelic loss of the wild-type Lkb1 was not the cause of polyp formation. Moreover, the LKB1 protein level was not reduced in hamartomatous polyps compared with that in the Lkb1 (+/-) normal gastric mucosa. In addition, the remaining allele showed neither missense mutations in the coding sequence nor produced truncated LKB1 in the hamartoma. Taken together, these data suggest that the wild-type Lkb1 is expressed in the hamartoma at the haploid amount. Accordingly, the gastrointestinal hamartomas appear to develop because of the Lkb1 haploinsufficiency. Although additional genetic events may be critical in hamartoma and adenocarcinoma development, these data strongly suggest that the initiation of polyposis is not the result of loss of heterozygosity in Lkb1.

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