Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes.
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.
Zhou
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XP
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.
Woodford-Richens
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Lehtonen
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Kurose
K
K
Aldred
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M
Hampel
H
H
Launonen
V
V
Virta
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Pilarski
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Salovaara
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Bodmer
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Conrad
B A
BA
Dunlop
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Hodgson
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Iwama
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Järvinen
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Kellokumpu
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Kim
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Leggett
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B
Markie
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D
Mecklin
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JP
Neale
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Phillips
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Piris
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Rozen
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Houlston
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RS
Aaltonen
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Tomlinson
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Eng
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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
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