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STK11 status and intussusception risk in Peutz-Jeghers syndrome.

ABSTRACT: BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by germline STK11 mutations and characterised by gastrointestinal polyposis. Although small bowel intussusception is a recognised complication of PJS, risk varies between patients. OBJECTIVE: To analyse the time to onset of intussusception in a large series of PJS probands. METHODS: STK11 mutation status was evaluated in 225 PJS probands and medical histories of the patients reviewed. RESULTS: 135 (60%) of the probands possessed a germline STK11 mutation; 109 (48%) probands had a history of intussusception at a median age of 15.0 years but with wide variability (range 3.7 to 45.4 years). Median time to onset of intussusception was not significantly different between those with identified mutations and those with no mutation detected, at 14.7 years and 16.4 years, respectively (log-rank test of difference, chi(2) = 0.58, with 1df; p = 0.45). Similarly no differences were observed between patient groups on the basis of the type or site of STK11 mutation. CONCLUSIONS: The risk of intussusception in PJS is not influenced by STK11 mutation status.

SUBMITTER: Hearle N

PROVIDER: S-EPMC2564597 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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STK11 status and intussusception risk in Peutz-Jeghers syndrome.

Hearle N N Schumacher V V Menko F H FH Olschwang S S Boardman L A LA Gille J J P JJ Keller J J JJ Westerman A M AM Scott R J RJ Lim W W Trimbath J D JD Giardiello F M FM Gruber S B SB Offerhaus G J A GJ Rooij F W M D E FW Wilson J H P JH Hansmann A A Möslein G G Royer-Pokora B B Vogel T T Phillips R K S RK Spigelman A D AD Houlston R S RS

Journal of medical genetics 20060801 8

<h4>Background</h4>Peutz-Jeghers syndrome (PJS) is caused by germline STK11 mutations and characterised by gastrointestinal polyposis. Although small bowel intussusception is a recognised complication of PJS, risk varies between patients.<h4>Objective</h4>To analyse the time to onset of intussusception in a large series of PJS probands.<h4>Methods</h4>STK11 mutation status was evaluated in 225 PJS probands and medical histories of the patients reviewed.<h4>Results</h4>135 (60%) of the probands p ...[more]

PMID: 16882735

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Project description:BackgroundPeutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disease resulting in multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation, and an increased risk of various types of cancer, and is caused by variations in the serine/threonine protein kinase STK11 (LKB1).MethodsSTK11 gene variations were identified by analyzing STK11 cDNA and genomic DNA. Minigenes carrying the wild-type and mutant sequences were subjected to in vitro splicing assay to dissect the features of these mutations. The different distribution of wild-type and mutant protein in cells were tested by Immunofluorescence assays and the functional analysis of the variation were performed using Western blot.ResultsA novel heterozygous splice-acceptor site variation (c.921-2 A>C) in intron 7 of the STK11 gene which is co-segregates with the PJS phenotypes in the proband and all the affected family members and three previously reported variations (c.180C>G, c.580G>A, c.787_790del) were identified in the four families. The c.921-2 A>C substitution resulted in the inactivation of a splice site and the utilization of a cryptic splice acceptor site surrounding exon 8, generating three different aberrant RNA transcripts, leading to frameshift translation and protein truncation. The results of minigenes indicated that the spliceosome can use a variety of 3' acceptor site sequences to pair with a given 5' donor site. The immunofluorescent visualization showed that the distribution of mutant STK11 was different from that of wild-type STK11, suggesting the mutation may be the causative effect on the dysfunction of the mutant protein. The rescue experiments indicated that the failure of suppressing mTOR phosphorylation by shRNA STK11 could be eliminated by supply of wild-type STK11 rather than mutant STK11.ConclusionWe identified a novel heterozygous mutation (c.921-2 A>C) in the STK11 in a Chinese PJS family. Haploinsufficiency of STK11 might contribute to the pathogenesis of the disease.

Dataset Information

STK11 status and intussusception risk in Peutz-Jeghers syndrome.

Publications

STK11 status and intussusception risk in Peutz-Jeghers syndrome.

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