title: Genetic defects underlying Peutz-Jeghers syndrome (PJS) and exclusion of the polarity-associated MARK/Par1 gene family as potential PJS candidates.
abstract: LKB1/STK11 germline inactivations are identified in the majority (66-94%) of Peutz-Jeghers syndrome (PJS) patients. Therefore, defects in other genes or so far unidentified ways of LKB1 inactivation may cause PJS. The genes encoding the MARK proteins, homologues of the Par1 polarity protein that associates with Par4/Lkb1, were analyzed in this study because of their link to LKB1 and cell polarity. The genetic defect underlying PJS was determined through analysis of both LKB1 and all four MARK genes. LKB1 point mutations and small deletions were identified in 18 of 23 PJS families using direct sequencing and multiplex ligation-dependent probe amplification analysis identified exon deletions in 3 of 23 families. In total, 91% of the studied families showed LKB1 inactivation. Furthermore, a MARK1, MARK2, MARK3 and MARK4 mutation analysis and an MARK4 quantitative multiplex polymerase chain reaction analysis to identify exon deletions on another eight PJS families without identified LKB1 germline mutation did not identify mutations in the MARK genes. LKB1 defects are the major cause of PJS and genes of the MARK family do not represent alternative PJS genes. Other mechanisms of inactivation of LKB1 may cause PJS in the remaining families.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. w.w.j.deleng@umcutrecht.nl
authors.forename: W W J
authors.initials: WW
authors.lastname: de Leng
authors.forename: M
authors.initials: M
authors.lastname: Jansen
authors.forename: R
authors.initials: R
authors.lastname: Carvalho
authors.forename: M
authors.initials: M
authors.lastname: Polak
authors.forename: A R
authors.initials: AR
authors.lastname: Musler
authors.forename: A N A
authors.initials: AN
authors.lastname: Milne
authors.forename: J J
authors.initials: JJ
authors.lastname: Keller
authors.forename: F H
authors.initials: FH
authors.lastname: Menko
authors.forename: F W M
authors.initials: FW
authors.lastname: de Rooij
authors.forename: C A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.forename: F M
authors.initials: FM
authors.lastname: Giardiello
authors.forename: M A J
authors.initials: MA
authors.lastname: Weterman
authors.forename: G J A
authors.initials: GJ
authors.lastname: Offerhaus
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D005091:Exons; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007438:Introns; D008297:Male; D005810:Multigene Family; D010580:Peutz-Jeghers Syndrome / Q000201:enzymology / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases