title: Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes.
abstract: Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor beta-receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype.
authors.affiliation: Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and the Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: X P
authors.initials: XP
authors.lastname: Zhou
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authors.lastname: Woodford-Richens
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authors.lastname: Lehtonen
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authors.lastname: Kurose
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authors.lastname: Aldred
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authors.lastname: Hampel
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authors.lastname: Launonen
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authors.lastname: Virta
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authors.lastname: Pilarski
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authors.lastname: Salovaara
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authors.lastname: Bodmer
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authors.initials: BA
authors.lastname: Conrad
authors.forename: M
authors.initials: M
authors.lastname: Dunlop
authors.forename: S V
authors.initials: SV
authors.lastname: Hodgson
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authors.lastname: Iwama
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authors.lastname: Järvinen
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authors.lastname: Kellokumpu
authors.forename: J C
authors.initials: JC
authors.lastname: Kim
authors.forename: B
authors.initials: B
authors.lastname: Leggett
authors.forename: D
authors.initials: D
authors.lastname: Markie
authors.forename: J P
authors.initials: JP
authors.lastname: Mecklin
authors.forename: K
authors.initials: K
authors.lastname: Neale
authors.forename: R
authors.initials: R
authors.lastname: Phillips
authors.forename: J
authors.initials: J
authors.lastname: Piris
authors.forename: P
authors.initials: P
authors.lastname: Rozen
authors.forename: R S
authors.initials: RS
authors.lastname: Houlston
authors.forename: L A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: I P
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: C
authors.initials: C
authors.lastname: Eng
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D052005:Bone Morphogenetic Protein Receptors, Type I; D003110:Colonic Neoplasms / Q000150:complications / Q000235:genetics; D004252:DNA Mutational Analysis; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006223:Hamartoma Syndrome, Multiple / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007417:Intestinal Polyps / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D019656:Loss of Heterozygosity / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics*; D013577:Syndrome
chemical_list: D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I