High prevalence of germline STK11mutations in Hungarian Peutz-Jeghers Syndrome patients

Abstract

BackgroundPeutz-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.MethodsMutation 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.ResultsThirteen 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.ConclusionsA 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.

Unusually Early Presentation of Small-Bowel Adenocarcinoma in a Patient With Peutz-Jeghers Syndrome

“…As molecular technology has advanced, cases which were previously classified as “ STK11 negative” were noted to be due to STK11 deletions which were not detected by sequencing methods 5 . Recent studies combining diagnostic methods sensitive to deletions and point mutations have suggested that all cases may be due to some type of STK11 mutation 6, 7 . The genotype-phenotype correlation in PJS is complex but higher cancer risk may be associated with mutations in exon 3 or premature truncation alleles 8 While STK11 is the only known gene, there are also no reported cases in which an individual with an STK11 mutation does not show clinical manifestations leading some authors to suggest that these mutations are fully penetrant 6 .…”

Peutz-Jeghers syndrome: early clinical expression of a new STK11 gene variant

“…The gene STK11 includes 22637 base pairs and 10 exons, 9 of which contain a coding sequence of 48.6 kDa protein, which fulfils the function of serine-threonine kinase 3 6. It is a suppressor gene, and the kinase encoded by it plays an important role in cell metabolism regulation and proliferation, cell polarity, p53-mediated apoptosis and in other signalling pathways 3 6 9…”

“…There is no family history of PJS in approximately 45% of patients,3 6 but the exact proportion of de novo gene mutations is still unknown 3 6 9. Thus family testing is important.…”

Hereditary gynecological tumors associated with Peutz-Jeghers syndrome (Review)

“…The gene that is responsible for causing PJS is the tumor suppressor gene, STK11/LKB1 , which is located on the short arm of chromosome 19 (19p13.3) (12). The gene is 23 kb in size and is comprised of nine coding exons and one non-coding exon.…”