title: The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.
abstract: BACKGROUND
  Juvenile polyposis (JP) is an autosomal dominant syndrome predisposing to colorectal and gastric cancer. We have identified mutations in two genes causing JP, MADH4 and bone morphogenetic protein receptor 1A (BMPR1A): both are involved in bone morphogenetic protein (BMP) mediated signalling and are members of the TGF-beta superfamily. This study determined the prevalence of mutations in MADH4 and BMPR1A, as well as three other BMP/activin pathway candidate genes in a large number of JP patients.
  
  
  METHODS
  DNA was extracted from the blood of JP patients and used for PCR amplification of each exon of these five genes, using primers flanking each intron-exon boundary. Mutations were determined by comparison to wild type sequences using sequence analysis software. A total of 77 JP cases were sequenced for mutations in the MADH4, BMPR1A, BMPR1B, BMPR2, and/or ACVR1 (activin A receptor) genes. The latter three genes were analysed when MADH4 and BMPR1A sequencing found no mutations.
  
  
  RESULTS
  Germline MADH4 mutations were found in 14 cases (18.2%) and BMPR1A mutations in 16 cases (20.8%). No mutations were found in BMPR1B, BMPR2, or ACVR1 in 32 MADH4 and BMPR1A mutation negative cases.
  
  
  CONCLUSIONS
  In the largest series of JP patients reported to date, the prevalence of germline MADH4 and BMPR1A mutations is approximately 20% for each gene. Since mutations were not found in more than half the JP patients, either additional genes predisposing to JP remain to be discovered, or alternate means of inactivation of the two known genes are responsible for these JP cases.
authors.affiliation: Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242-1086, USA. james-howe@uiowa.edu
authors.forename: J R
authors.initials: JR
authors.lastname: Howe
authors.forename: M G
authors.initials: MG
authors.lastname: Sayed
authors.forename: A F
authors.initials: AF
authors.lastname: Ahmed
authors.forename: J
authors.initials: J
authors.lastname: Ringold
authors.forename: J
authors.initials: J
authors.lastname: Larsen-Haidle
authors.forename: A
authors.initials: A
authors.lastname: Merg
authors.forename: F A
authors.initials: FA
authors.lastname: Mitros
authors.forename: C A
authors.initials: CA
authors.lastname: Vaccaro
authors.forename: G M
authors.initials: GM
authors.lastname: Petersen
authors.forename: F M
authors.initials: FM
authors.lastname: Giardiello
authors.forename: S T
authors.initials: ST
authors.lastname: Tinley
authors.forename: L A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: H T
authors.initials: HT
authors.lastname: Lynch
mesh_terms: D030201:Activin Receptors, Type I; D011125:Adenomatous Polyposis Coli / Q000453:epidemiology* / Q000235:genetics*; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D003110:Colonic Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D006801:Humans; D017720:Molecular Epidemiology / Q000379:methods; D015995:Prevalence; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000235:genetics*; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; D017978:Receptors, Growth Factor; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; C498211:BMPR1A protein, human; C498214:BMPR1B protein, human; C498218:BMPR2 protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II