Large deletions and splicing-site mutations inthe STK11 gene in Peutz-Jeghers Chilean families
ABSTRACT Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by mucocutaneous melanocytic macules, gastrointestinal hamartomatous polyposis and an increased risk of various neoplasms. Germline mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a cause for PJS. The aim of this study was to characterize the genotype of Chilean PJS patients. Mutation screening of 13 patients from eight PJS families was performed using a single strand conformation polymorphism analysis, DNA sequencing and multiplex ligation-dependent probe amplification assay. The breakpoints of the genomic rearrangements were assessed by a long-range polymerase chain reaction and sequencing. The results revealed the existence of seven different pathogenic mutations in STK11 gene in seven unrelated families, including three point mutations and four large genomic deletions. Three of these point mutations (43%, 3/7) may be considered as novel. Our results showed that a germline mutation is present in STK11 in 88% of probands fulfilling the diagnostic criteria of PJS. In this study, the combination of two different experimental approaches in the screening of the STK11 in PJS, led to a higher percentage of mutation detection.
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ABSTRACT: We identified a family in which five siblings were diagnosed with multiple sclerosis (MS) or clinically isolated syndrome. Several women in the maternal lineage have comorbidities typically associated with Peutz Jeghers Syndrome, a rare autosomal-dominant disease caused by mutations in the serine-threonine-kinase 11 (STK11) gene, which encodes liver kinase B1. Sequence analysis of DNA from one sibling identified a single-nucleotide polymorphism (SNP) within STK11 intron 5. This SNP (dbSNP ID: rs9282860) was identified by TaqMan polymerase chain reaction (PCR) assays in DNA samples available from two other siblings. Further screening was carried out in samples from 654 relapsing-remitting MS patients, 100 primary progressive MS patients, and 661 controls. The STK11-SNP has increased frequency in all female patients versus controls (odds ratio = 1.66, 95% CI = 1.05, 2.64, p = .032). The STK11-SNP was not associated with disease duration or onset; however, it was significantly associated with reduced severity (assessed by MS severity scores), with the lowest scores in patients who also harbored the HLA-DRB1*1501 allele. In vitro studies showed that peripheral blood mononuclear cells from members of the family were more sensitive to the mitochondrial inhibitor metformin than cells from MS patients with the major STK11 allele. The increased association of SNP rs9282860 in women with MS defines this variant as a genetic risk factor. The lower disease severity observed in the context of HLA-DRB1*1501 combined with limited in vitro studies raises the provocative possibility that cells harboring the STK11-SNP could be targeted by drugs which increase metabolic stress. © The Author(s) 2015.ASN Neuro 02/2015; 7(1). DOI:10.1177/1759091415568914 · 4.44 Impact Factor
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ABSTRACT: 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. PJS is preconditioned by the manifestation of mutations in the STK11 gene. The majority of detected STK11 changes are small scale mutations, however recent studies showed the significant contribution of medium-sized changes commonly known as copy number variations (CNVs). Here we present a novel 7001 bps deletion of STK11 gene fragment, in which we identified the presence of breakpoints (BPs) within the Alu elements. Comparative meta-analysis with the 80 other CNV cases from 12 publications describing STK11 mutations in patients with PJS revealed the participation of specific Alu elements in all deletions of exons 2-3 so far described. Moreover, we have shown their involvement in the two other CNVs, deletion of exon 2 and deletion of exon 1-3 respectively. Deletion of exons 2-3 of the STK11 gene may prove to be the most recurrent large rearrangement causing PJS. In addition, the sequences present in its BPs may be involved in a formation of a significant percentage of the remaining gene CNVs. This gives a new insight into the conditioning of this rare disease and enables improvements in PJS genetic diagnostics.Familial Cancer 04/2015; DOI:10.1007/s10689-015-9800-5 · 1.62 Impact Factor