Mutations in STK11 gene in Czech Peutz-Jeghers patients

Department of Biology and Medical Genetics, Charles University 2nd Medical School, University Hospital Motol, Prague, Czech Republic.
BMC Medical Genetics (Impact Factor: 2.08). 08/2009; 10(1):69. DOI: 10.1186/1471-2350-10-69
Source: PubMed


Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary disease characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyposis. The germline mutations in the serine/threonine kinase 11 (STK11) gene have been shown to be associated with the disease. Individuals with PJS are at increased risk for development of various neoplasms. The aim of the present study was to characterize the genotype and phenotype of Czech patients with PJS.
We examined genomic DNA of 8 individuals from five Czech families by sequencing analysis of STK11 gene, covering its promotor region, the entire coding region and the splice-site boundaries, and by multiplex ligation-dependent probe amplification (MLPA) assay designed for the identification of large exonic deletions or duplications of STK11 gene.
We found pathogenic mutations in STK11 gene in two families fulfilling the diagnostic criteria of PJS and in one of three sporadic cases not complying with the criteria. The patient with the frameshift mutation in STK11 gene developed aggressive gastric cancer. No other studied proband has developed a carcinoma so far.
Our results showed that a germline mutation of STK11 gene can be found not only in probands fulfilling the PJS diagnostic criteria, but also in some sporadic cases not complying with the criteria. Moreover, we observed a new case of aggressive gastric cancer in a young patient with a frameshift mutation of STK11 gene.

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    • "STK11 point mutations account for the large majority of PJS cases whereas large deletions account for up to 30% of the cases [37]. STK11 mutations can be found in familial PJS and in some sporadic cases as well [38]. "
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    ABSTRACT: Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients. Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed. 25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal polyps. 72% required urgent surgery due to intestinal obstruction. 3 families had multiple cases of seizure disorder, representing 20% of cases. 28% developed cancer and two patients had more than one cancer. An STK11 mutation was found in 8 of the 9 families analyzed. A unique M136K missense mutation was noted in one family. Comparing annual live births and PJS birth records from 1970 to 2009 yielded an incidence of 1 in 155,000. The Uruguayan Registry for Peutz-Jeghers patients showed a high chance of emergent surgery, epilepsy, cancer and shortened life expectancy. The M136K missense mutation is a newly reported STK 11 mutation.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "In the studies of other populations the most common method used for the detection of small mutations in PJS patients is direct sequencing [8,17,22,24,25]. Only in few studies Denaturing High Performance Liquid Chromatography (DHPLC) [8] or older screening techniques such as DGGE, SSCP and HA were also used [26,27]. "
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    ABSTRACT: Background Peutz-Jeghers syndrome (PJS) is a rare hereditary syndrome characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation and increased risk of cancer in multiple internal organs. Depending on the studied population, its incidence has been estimated to range from 1:200 000 even up to 1:50 000 births. Being an autosomal disease, PJS is caused in most cases by mutations in the STK11 gene. Methods The majority of causative DNA changes identified in patients with PJS are small mutations and, therefore, developing a method of their detection is a key aspect in the advancement of genetic diagnostics of PJS patients. We designed 13 pairs of primers, which amplify at the same temperature and enable examination of all coding exons of the STK11 gene by the HRM analysis. Results In our group of 41 families with PJS small mutations of the STK11 gene were detected in 22 families (54%). In the remaining cases all of the coding exons were sequenced. However, this has not allowed to detect any additional mutations. Conclusions The developed methodology is a rapid and cost-effective screening tool for small mutations in PJS patients and makes it possible to detect all the STK11 gene sequence changes occurring in this group.
    Full-text · Article · May 2013 · BMC Medical Genetics
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    • "In this study we identified deleterious sequence alterations in all 13 PJS families studied, including point mutations (8/13, 62%) as well as large genomic deletions removing from one to several exons of the gene (5/13, 38%). This high fraction of large genomic aberrations identified in Hungarian patients is in agreement with the proportions seen in several other populations [18,19,28,29]. Only one of the point mutations uncovered in our cohort (c.180C>A; p.Tyr60X) can be found in the publicly available version of The Human Genome Mutation Database [30,31], all other point mutations can be considered novel. "
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    ABSTRACT: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disease characterized by gastrointestinal hamartomatous polyposis and mucocutaneous pigmentation. The genetic predisposition for PJS has been shown to be associated with germline mutations in the STK11/LKB1 tumor suppressor gene. The aim of the present study was to characterize Hungarian PJS patients with respect to germline mutation in STK11/LKB1 and their association to disease phenotype. Mutation screening of 21 patients from 13 PJS families were performed using direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). Comparative semi-quantitative sequencing was applied to investigate the mRNA-level effects of nonsense and splice-affecting mutations. Thirteen different pathogenic mutations in STK11, including a high frequency of large genomic deletions (38%, 5/13), were identified in the 13 unrelated families studied. One of these deletions also affects two neighboring genes (SBNO2 and GPX4), located upstream of STK11, with a possible modifier effect. The majority of the point mutations (88%, 7/8) can be considered novel. Quantification of the STK11 transcript at the mRNA-level revealed that the expression of alleles carrying a nonsense or frameshift mutation was reduced to 30-70% of that of the wild type allele. Mutations affecting splice-sites around exon 2 displayed an mRNA processing pattern indicative of co-regulated splicing of exons 2 and 3. A combination of sensitive techniques may assure a high (100%) STK11 mutation detection frequency in PJS families. Characterization of mutations at mRNA level may give a deeper insight into the molecular consequences of the pathogenic mutations than predictions made solely at the genomic level.
    Full-text · Article · Nov 2010 · BMC Medical Genetics
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