Evaluation of germline BMP4 mutation as a cause of colorectal cancer

Steven J. Lubbe, Alan M. Pittman, Cornelis Matijssen, Philip Twiss, Bianca Olver, Amy Lloyd, Mobshra Qureshi, Nathan Brown, Emma Nye, Gordon Stamp, Julian Blagg, Richard S. Houlston*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Transforming growth factor-â (TGF-â) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-â family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for mutations in the coding sequence of BMP4. We identified three pathogenic mutations, p.R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C), amongst the CRC cases which were not observed in 524 healthy controls. p.R286X localizes to the N-terminal of the TGF-â1 prodomain truncating the protein prior to the active domain. p.W325C and p.C373S mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function. Segregation of p.C373S with adenoma and hyperplastic polyp in first-degree relatives of the case suggests germline mutations may confer a juvenile polyposis-type phenotype. These findings suggest mutation of BMP4is a cause of CRC and the value of protein-based modelling in the elucidation of rare disease-causing variants.

Original languageEnglish (US)
Pages (from-to)E1928-E1938
JournalHuman mutation
Issue number1
StatePublished - Jan 2011


  • BMP4
  • Bone morphogenetic protein-4
  • Colorectal cancer
  • Rare mutations

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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