SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility

Huiling He, Agnieszka Bronisz, Sandya Liyanarachchi, Rebecca Nagy, Wei Li, Yungui Huang, Keiko Akagi, Motoyasu Saji, Dorota Kula, Anna Wojcicka, Nikhil Sebastian, Bernard Wen, Zbigniew Puch, Michal Kalemba, Elzbieta Stachlewska, Malgorzata Czetwertynska, Joanna Dlugosinska, Kinga Dymecka, Rafal Ploski, Marek KrawczykPatrick J. Morrison, Matthew D. Ringel, Richard T. Kloos, Krystian Jazdzewski, David E. Symer, Veronica J. Vieland, Michael Ostrowski, Barbara Jarzab, Albert De La Chapelle

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E973-E980
JournalJournal of Clinical Endocrinology and Metabolism
Volume98
Issue number5
DOIs
StatePublished - May 2013
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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