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Three novel mutations of STK11 gene in Chinese patients with Peutz-Jeghers syndrome.

ABSTRACT: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous hyperpigmentation, and an increased risk of cancer. Mutations in the serine-threonine kinase 11 gene (SKT11) are the major cause of PJS.Blood samples were collected from six PJS families including eight patients. Mutation screening of STK11 gene was performed in these six families by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) assay. Three novel mutations (c.721G?>?C, c.645_726del82, and del(exon2-5)) and three recurrent mutations (c.752G?>?A, c.545 T?>?C and del(exon1)) in STK11 were detected in six Chinese PJS families. Genotype-phenotype correlations suggested that truncating mutations trend to result in severe complications.These findings broaden the mutation spectrum of the STK11 gene and would help clinicians and genetic counselors provide better clinical surveillance for PJS patients, especially for ones carrying truncating mutation.

SUBMITTER: Tan H

PROVIDER: S-EPMC5100203 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Three novel mutations of STK11 gene in Chinese patients with Peutz-Jeghers syndrome.

Tan Hu H Mei Libin L Huang Yanru Y Yang Pu P Li Haoxian H Peng Ying Y Chen Chen C Wei Xianda X Pan Qian Q Liang Desheng D Wu Lingqian L

BMC medical genetics 20161108 1

<h4>Background</h4>Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous hyperpigmentation, and an increased risk of cancer. Mutations in the serine-threonine kinase 11 gene (SKT11) are the major cause of PJS.<h4>Case presentation</h4>Blood samples were collected from six PJS families including eight patients. Mutation screening of STK11 gene was performed in these six families by Sanger sequencing ...[more]

PMID: 27821076

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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

Three novel mutations of STK11 gene in Chinese patients with Peutz-Jeghers syndrome.

Publications

Three novel mutations of STK11 gene in Chinese patients with Peutz-Jeghers syndrome.

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