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: 2.45). 08/2009; 10:69. DOI: 10.1186/1471-2350-10-69
Source: PubMed

ABSTRACT 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.


Available from: Peter Vasovcak, Jun 13, 2015
  • Source
    [Show abstract] [Hide abstract]
    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.
    PLoS ONE 11/2013; 8(11):e79639. DOI:10.1371/journal.pone.0079639 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    BMC Medical Genetics 05/2013; 14(1):58. DOI:10.1186/1471-2350-14-58 · 2.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Peutz Jeghers syndrome (PJS) is an autosomal dominant disease caused by mutations in the LKB1 gene. We screened for the LKB1 gene mutation in a Chinese PJS patient. Sequence analysis of LKB1 exons showed that there was a novel de novo mis-sense mutation of codon 16 (GAG to GGG) in exon 1 in LKB1 gene in the Chinese PJS patient. Furthermore, we observed that wild type LKB1 expression increased p53 activity, while LKB1 A47G mutation had no such effect on p53 activity, indicating that the mis-sense variant of LKB1 influenced the p53 activation function of LKB1 protein. In addition, real-time RT-PCR analysis revealed that the expression levels of p53 downstream targets were significantly diminished in affected PJS patient compared with those in unaffected parents, further confirming the roles of LKB1 and p53 in PJS pathogenesis. Therefore, a novel PJS associated LKB1 gene mutation is provided, and the roles of LKB1 and p53 in PJS pathogenesis is validated in this research.
    Gastroentérologie Clinique et Biologique 03/2011; 35(3):221-6. DOI:10.1016/j.clinre.2010.11.008 · 1.98 Impact Factor