High prevalence of germline STK11 mutations in Hungarian Peutz-Jeghers Syndrome patients.
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.
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
Janos
J
Papp
Marietta Eva
ME
Kovacs
Szilvia
S
Solyom
Miklos
M
Kasler
Anne-Lise
AL
Børresen-Dale
Edith
E
Olah
D000091162:AMP-Activated Protein Kinase Kinases; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D006814:Hungary; D008297:Male; D008875:Middle Aged; D010580:Peutz-Jeghers Syndrome / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*
D018389:Codon, Nonsense; D022821:RNA Splice Sites; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases