High prevalence of germline STK11 mutations in Hungarian Peutz-Jeghers Syndrome patients

J. Papp, Marietta E. Kovacs, Szilvia Solyom, M. Kásler, Anne Lise Børresen-Dale, E. Oláh

Research output: Contribution to journalArticle

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Abstract

Background: 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.Methods: 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.Results: 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.Conclusions: 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.

Original languageEnglish
Article number169
JournalBMC Medical Genetics
Volume11
Issue number1
DOIs
Publication statusPublished - Nov 30 2010

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Peutz-Jeghers Syndrome
Germ-Line Mutation
Mutation
Messenger RNA
Exons
Alleles
Frameshift Mutation
Nonsense Codon
Gastrointestinal Diseases
Multiplex Polymerase Chain Reaction
Pigmentation
Mutation Rate
Genetic Predisposition to Disease
Tumor Suppressor Genes
DNA Sequence Analysis
Point Mutation
Phenotype
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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High prevalence of germline STK11 mutations in Hungarian Peutz-Jeghers Syndrome patients. / Papp, J.; Kovacs, Marietta E.; Solyom, Szilvia; Kásler, M.; Børresen-Dale, Anne Lise; Oláh, E.

In: BMC Medical Genetics, Vol. 11, No. 1, 169, 30.11.2010.

Research output: Contribution to journalArticle

Papp, J. ; Kovacs, Marietta E. ; Solyom, Szilvia ; Kásler, M. ; Børresen-Dale, Anne Lise ; Oláh, E. / High prevalence of germline STK11 mutations in Hungarian Peutz-Jeghers Syndrome patients. In: BMC Medical Genetics. 2010 ; Vol. 11, No. 1.
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abstract = "Background: 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.Methods: 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.Results: 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.Conclusions: 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.",
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