title: A family with juvenile polyposis linked to the BMPR1A locus: cryptic mutation or closely linked gene?
abstract: OBJECTIVE
  Familial juvenile polyposis syndrome (JPS) is a rare autosomal dominant condition in which patients develop hamartomatous gastrointestinal polyps with malignant potential. Pathogenic germline mutations in both the SMAD4 and BMPR1A genes involved in the transforming growth factor beta pathway account for 40% of cases of JPS. Genetic heterogeneity remains evident, as the balance of cases is not accounted for by mutations in these genes. The aim of this study was to determine the mutation responsible in a family with juvenile polyposis.
  
  
  METHODS
  An Australian Caucasian family with juvenile polyposis have attended and followed surveillance plans through the Familial Bowel Cancer Clinic, The Royal Melbourne Hospital. A pedigree of the family was constructed with attention to the mixed phenotypic expression of polyps in affected members. Genetic testing for SMAD4 and BMPR1A mutations in germline DNA and linkage analysis to SMAD4, BMPR1A and 15q14 (CRAC1 locus) were performed.
  
  
  RESULTS
  There were no pathogenic mutations in SMAD4 and BMPR1A. There was no linkage to SMAD4 or 15q14 (CRAC1 locus). Linkage analysis suggested a cryptic BMPR1A mutation or the presence of another gene in close proximity to the BMPR1A locus. Two additional candidate genes in the region of linkage (PTEN and MINPP1) were excluded.
  
  
  CONCLUSIONS
  Most affected members of this Australian Caucasian family demonstrate a phenotype of mixed polyps: juvenile polyps, adenomas and/or hyperplastic polyps. Cloning of a potentially responsible gene closely linked to the BMPR1A locus or a cryptic mutation in BMPR1A may offer valuable insights into the pathogenesis of JPS.
authors.affiliation: Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia. elizabethchow@yahoo.com
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chow
authors.forename: Lara
authors.initials: L
authors.lastname: Lipton
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
authors.forename: Gordon
authors.initials: G
authors.lastname: Arthur
authors.forename: Prithi
authors.initials: P
authors.lastname: Bhathal
authors.forename: Gurjeet
authors.initials: G
authors.lastname: Kaur
authors.forename: Emma
authors.initials: E
authors.lastname: Jaeger
authors.forename: Kelly
authors.initials: K
authors.lastname: Woodford-Richens
authors.forename: Kimberley
authors.initials: K
authors.lastname: Howarth
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Finlay
authors.initials: F
authors.lastname: Macrae
mesh_terms: D000328:Adult; D000368:Aged; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D005190:Family; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D044483:Intestinal Polyposis / Q000453:epidemiology / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D051901:Smad4 Protein / Q000235:genetics
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I