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The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations
  1. J R Howe1,
  2. M G Sayed1,
  3. A F Ahmed1,
  4. J Ringold1,
  5. J Larsen-Haidle2,
  6. A Merg1,
  7. F A Mitros3,
  8. C A Vaccaro4,
  9. G M Petersen5,
  10. F M Giardiello6,
  11. S T Tinley7,
  12. L A Aaltonen8,
  13. H T Lynch7
  1. 1Department of Surgery, University of Iowa College of Medicine, Iowa City, IA, USA
  2. 2Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA, USA
  3. 3Department of Pathology, University of Iowa College of Medicine, Iowa City, IA, USA
  4. 4Section of Colorectal Surgery, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
  5. 5Department of Clinical Epidemiology, Mayo Clinic, Rochester, MN, USA
  6. 6Oncology Center, Johns Hopkins University, Baltimore, MD, USA
  7. 7Department of Preventive Medicine, Creighton University, Omaha, NE, USA
  8. 8Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
  1. Correspondence to:
 Dr J R Howe
 Department of Surgery, 4644 JCP, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242-1086, USA;


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-β 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.

Discussion: 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.

  • BMP, bone morphogenetic protein
  • BMPR1A, bone morphogenetic protein receptor 1A gene
  • CS, Cowden syndrome
  • HHT, hereditary hemorrhagic telangiectasia
  • JP, juvenile polyposis
  • MH1, Mad Homology 1
  • BMP
  • BMPR1A
  • juvenile polyposis
  • MADH4
  • TGF-beta

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  • The generous support of the Roy J. Carver Foundation made these studies possible.

  • Conflict of interest: none declared.