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Novel mutations in the STK11 gene in Thai patients with Peutz-Jeghers syndrome.

ABSTRACT: Peutz-Jeghers syndrome (PJS), a rare autosomal dominant inherited disorder, is characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. Patients with this syndrome have a predisposition to a variety of cancers in multiple organs. Mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a major cause of PJS. Here we present the clinical and molecular findings of two unrelated Thai individuals with PJS. Mutation analysis by Polymerase Chain Reaction-sequencing of the entire coding region of STK11 revealed two potentially pathogenic mutations. One harbored a single nucleotide deletion (c.182delG) in exon 1 resulting in a frameshift leading to premature termination at codon 63 (p.Gly61AlafsX63). The other carried an in-frame 9-base-pair (bp) deletion in exon 7, c.907_915del9 (p.Ile303_Gln305del). Both deletions were de novo and have never been previously described. This study has expanded the genotypic spectrum of the STK11 gene.

SUBMITTER: Ausavarat S

PROVIDER: S-EPMC2776867 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Novel mutations in the STK11 gene in Thai patients with Peutz-Jeghers syndrome.

Ausavarat Surasawadee S Leoyklang Petcharat P Vejchapipat Paisarn P Chongsrisawat Voranush V Suphapeetiporn Kanya K Shotelersuk Vorasuk V

World journal of gastroenterology 20091101 42

Peutz-Jeghers syndrome (PJS), a rare autosomal dominant inherited disorder, is characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. Patients with this syndrome have a predisposition to a variety of cancers in multiple organs. Mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a major cause of PJS. Here we present the clinical and molecular findings of two unrelated Thai individuals with PJS. Mutation analysis by Polymerase Chain Rea ...[more]

PMID: 19908348

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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

Novel mutations in the STK11 gene in Thai patients with Peutz-Jeghers syndrome.

Publications

Novel mutations in the STK11 gene in Thai patients with Peutz-Jeghers syndrome.

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