Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome.
OBJECTIVE
Juvenile polyps occur in several Mendelian disorders, whether in association with gastrointestinal cancer alone (juvenile polyposis syndrome, JPS) or as part of known syndromes (Cowden, Gorlin, and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in the SMAD4 (DPC4) gene, providing further evidence for the importance of the TGFbeta signalling pathway in colorectal cancer. There remains, however, considerable, unexplained genetic heterogeneity in JPS. Other members of the SMAD family are excellent candidates for JPS, especially SMAD2 (which, like SMAD4, is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when "knocked out" in mice), SMAD5, and SMAD1.


METHODS
SMAD1, SMAD2, SMAD3, and SMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4 mutations.


RESULTS
No mutations were found in any of these genes. A G-A C89Y polymorphism with possible effects on protein function was found in SMAD3, but the frequencies of the G and A alleles did not differ between patients with JPS and controls.


CONCLUSIONS
It remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas. SMAD4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.
Bevan
S
S
Section of Cancer Genetics, Haddow Laboratories, Institute of Cancer Research, Sutton, UK.
Woodford-Richens
K
K
Rozen
P
P
Eng
C
C
Young
J
J
Dunlop
M
M
Neale
K
K
Phillips
R
R
Markie
D
D
Rodriguez-Bigas
M
M
Leggett
B
B
Sheridan
E
E
Hodgson
S
S
Iwama
T
T
Eccles
D
D
Bodmer
W
W
Houlston
R
R
Tomlinson
I
I
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000293:Adolescent; D004268:DNA-Binding Proteins / Q000235:genetics*; D005819:Genetic Markers; D018095:Germ-Line Mutation; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics; D011110:Polymorphism, Genetic; D051785:Smad Proteins; D051898:Smad1 Protein; D051899:Smad2 Protein; D051900:Smad3 Protein; D051902:Smad5 Protein; D015534:Trans-Activators / Q000235:genetics
D004268:DNA-Binding Proteins; D005819:Genetic Markers; D010750:Phosphoproteins; C497399:SMAD1 protein, human; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497797:SMAD5 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D051899:Smad2 Protein; D051900:Smad3 Protein; D051902:Smad5 Protein; D015534:Trans-Activators