TY - JOUR
T1 - SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility
AU - He, Huiling
AU - Bronisz, Agnieszka
AU - Liyanarachchi, Sandya
AU - Nagy, Rebecca
AU - Li, Wei
AU - Huang, Yungui
AU - Akagi, Keiko
AU - Saji, Motoyasu
AU - Kula, Dorota
AU - Wojcicka, Anna
AU - Sebastian, Nikhil
AU - Wen, Bernard
AU - Puch, Zbigniew
AU - Kalemba, Michal
AU - Stachlewska, Elzbieta
AU - Czetwertynska, Malgorzata
AU - Dlugosinska, Joanna
AU - Dymecka, Kinga
AU - Ploski, Rafal
AU - Krawczyk, Marek
AU - Morrison, Patrick J.
AU - Ringel, Matthew D.
AU - Kloos, Richard T.
AU - Jazdzewski, Krystian
AU - Symer, David E.
AU - Vieland, Veronica J.
AU - Ostrowski, Michael
AU - Jarzab, Barbara
AU - De La Chapelle, Albert
PY - 2013/5
Y1 - 2013/5
N2 - Background: Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative. Objectives: The objective of this study was to identify susceptibility genes for PTC. Methods: A genome-wide linkage analysis was performed in 38 families. Targeted association study and screening were performed in 2 large cohorts of PTC patients and controls. Candidate DNA variants were tested in functional studies. Results: Linkage analysis and association studies identified the Slit-Robo Rho GTPase activating protein 1 gene (SRGAP1) in the linkage peak as a candidate gene. Two missense variants, Q149H and A275T, localized in the Fes/CIP4 homology domain segregated with the disease in 1 family each. One missense variant, R617C, located in the RhoGAP domain occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42, a key function of SRGAP1, was severely impaired by the Q149H and R617C variants. Conclusions: Our findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type.
AB - Background: Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative. Objectives: The objective of this study was to identify susceptibility genes for PTC. Methods: A genome-wide linkage analysis was performed in 38 families. Targeted association study and screening were performed in 2 large cohorts of PTC patients and controls. Candidate DNA variants were tested in functional studies. Results: Linkage analysis and association studies identified the Slit-Robo Rho GTPase activating protein 1 gene (SRGAP1) in the linkage peak as a candidate gene. Two missense variants, Q149H and A275T, localized in the Fes/CIP4 homology domain segregated with the disease in 1 family each. One missense variant, R617C, located in the RhoGAP domain occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42, a key function of SRGAP1, was severely impaired by the Q149H and R617C variants. Conclusions: Our findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type.
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U2 - 10.1210/jc.2012-3823
DO - 10.1210/jc.2012-3823
M3 - Article
C2 - 23539728
AN - SCOPUS:84877710417
SN - 0021-972X
VL - 98
SP - E973-E980
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 5
ER -