title: Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.
abstract: Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [juvenile polyposis syndrome (JPS)] and sometimes as part of known syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.
authors.affiliation: Cancer Genetics, Haddow Laboratories, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: R
authors.initials: R
authors.lastname: Houlston
authors.forename: S
authors.initials: S
authors.lastname: Bevan
authors.forename: A
authors.initials: A
authors.lastname: Williams
authors.forename: J
authors.initials: J
authors.lastname: Young
authors.forename: M
authors.initials: M
authors.lastname: Dunlop
authors.forename: P
authors.initials: P
authors.lastname: Rozen
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: D
authors.initials: D
authors.lastname: Markie
authors.forename: K
authors.initials: K
authors.lastname: Woodford-Richens
authors.forename: M A
authors.initials: MA
authors.lastname: Rodriguez-Bigas
authors.forename: B
authors.initials: B
authors.lastname: Leggett
authors.forename: K
authors.initials: K
authors.lastname: Neale
authors.forename: R
authors.initials: R
authors.lastname: Phillips
authors.forename: E
authors.initials: E
authors.lastname: Sheridan
authors.forename: S
authors.initials: S
authors.lastname: Hodgson
authors.forename: T
authors.initials: T
authors.lastname: Iwama
authors.forename: D
authors.initials: D
authors.lastname: Eccles
authors.forename: W
authors.initials: W
authors.lastname: Bodmer
authors.forename: I
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007417:Intestinal Polyps / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators