SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility

J Clin Endocrinol Metab. 2013 May;98(5):E973-80. doi: 10.1210/jc.2012-3823. Epub 2013 Mar 28.


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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma / genetics*
  • Carcinoma / metabolism
  • Carcinoma, Papillary
  • Cell Line, Tumor
  • Cohort Studies
  • Enzyme Activation
  • Family Health
  • Female
  • GTPase-Activating Proteins / chemistry
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • HEK293 Cells
  • Humans
  • Linkage Disequilibrium
  • Male
  • Mutation, Missense*
  • Ohio
  • Pedigree
  • Poland
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Thyroid Cancer, Papillary
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / metabolism
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism


  • GTPase-Activating Proteins
  • Protein Isoforms
  • Recombinant Proteins
  • SRGAP1 protein, human
  • cdc42 GTP-Binding Protein