The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations

J. R. Howe, M. G. Sayed, A. F. Ahmed, J. Ringold, J. Larsen-Haidle, A. Merg, F. A. Mitros, C. A. Vaccaro, G. M. Petersen, F. M. Giardiello, S. T. Tinley, L. A. Aaltonen, Henry T. Lynch

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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-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.

Original languageEnglish
Pages (from-to)484-491
Number of pages8
JournalJournal of Medical Genetics
Volume41
Issue number7
StatePublished - Jul 2004

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Bone Morphogenetic Protein Receptors
Mutation
Genes
Bone Morphogenetic Proteins
Exons
Activin Receptors
Activins
Germ-Line Mutation
Introns
Stomach Neoplasms
Sequence Analysis
Colorectal Neoplasms
Software
Cross-Sectional Studies

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Howe, J. R., Sayed, M. G., Ahmed, A. F., Ringold, J., Larsen-Haidle, J., Merg, A., ... Lynch, H. T. (2004). The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. Journal of Medical Genetics, 41(7), 484-491.

The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. / Howe, J. R.; Sayed, M. G.; Ahmed, A. F.; Ringold, J.; Larsen-Haidle, J.; Merg, A.; Mitros, F. A.; Vaccaro, C. A.; Petersen, G. M.; Giardiello, F. M.; Tinley, S. T.; Aaltonen, L. A.; Lynch, Henry T.

In: Journal of Medical Genetics, Vol. 41, No. 7, 07.2004, p. 484-491.

Research output: Contribution to journalArticle

Howe, JR, Sayed, MG, Ahmed, AF, Ringold, J, Larsen-Haidle, J, Merg, A, Mitros, FA, Vaccaro, CA, Petersen, GM, Giardiello, FM, Tinley, ST, Aaltonen, LA & Lynch, HT 2004, 'The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations', Journal of Medical Genetics, vol. 41, no. 7, pp. 484-491.
Howe JR, Sayed MG, Ahmed AF, Ringold J, Larsen-Haidle J, Merg A et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. Journal of Medical Genetics. 2004 Jul;41(7):484-491.
Howe, J. R. ; Sayed, M. G. ; Ahmed, A. F. ; Ringold, J. ; Larsen-Haidle, J. ; Merg, A. ; Mitros, F. A. ; Vaccaro, C. A. ; Petersen, G. M. ; Giardiello, F. M. ; Tinley, S. T. ; Aaltonen, L. A. ; Lynch, Henry T. / The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. In: Journal of Medical Genetics. 2004 ; Vol. 41, No. 7. pp. 484-491.
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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-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.",
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T1 - The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations

AU - Howe, J. R.

AU - Sayed, M. G.

AU - Ahmed, A. F.

AU - Ringold, J.

AU - Larsen-Haidle, J.

AU - Merg, A.

AU - Mitros, F. A.

AU - Vaccaro, C. A.

AU - Petersen, G. M.

AU - Giardiello, F. M.

AU - Tinley, S. T.

AU - Aaltonen, L. A.

AU - Lynch, Henry T.

PY - 2004/7

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N2 - 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.

AB - 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.

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