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A novel mutation in STK11 gene is associated with Peutz-Jeghers syndrome in Chinese patients.

ABSTRACT: BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by mutations in the tumor suppressor gene, STK11, and is characterized by gastrointestinal hamartomas, melanin spots on the lips, and an increased risk of developing cancer. METHODS: Blood samples were collected from two unrelated Chinese PJS families totaling 20 individuals (9 male and 11 females), including 6 PJS patients. The entire coding region of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing. RESULTS: A novel mutation, c.904C > T, in exon 7 was identified in both families. A C > T substitution changed codon 302 from CAG (glutamine) to TAG (stop), truncating the STK11 protein, thus leading to the partial loss of the kinase domain and complete loss of the ?-helix C-terminus. Furthermore, one PJS patient from each family was diagnosed with a visceral cancer, a colon cancer and a liver cancer respectively. CONCLUSION: We predict that this novel mutation, p.Q302X, is most likely responsible for development of the PJS phenotype and may even contribute to malignancy.

SUBMITTER: Wang Z

PROVIDER: S-EPMC3297525 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A novel mutation in STK11 gene is associated with Peutz-Jeghers syndrome in Chinese patients.

Wang Zhiqing Z Chen Yulan Y Wu Baoping B Zheng Haoxuan H He Jiman J Jiang Bo B

BMC medical genetics 20111214

<h4>Background</h4>Peutz-Jeghers syndrome (PJS) is caused by mutations in the tumor suppressor gene, STK11, and is characterized by gastrointestinal hamartomas, melanin spots on the lips, and an increased risk of developing cancer.<h4>Methods</h4>Blood samples were collected from two unrelated Chinese PJS families totaling 20 individuals (9 male and 11 females), including 6 PJS patients. The entire coding region of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct ...[more]

PMID: 22168747

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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

A novel mutation in STK11 gene is associated with Peutz-Jeghers syndrome in Chinese patients.

Publications

A novel mutation in STK11 gene is associated with Peutz-Jeghers syndrome in Chinese patients.

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