title: SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility.
abstract: BACKGROUND
  Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative.
  
  
  OBJECTIVE
  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.
authors.affiliation: Human Cancer Genetics Program and Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Comprehensive Cancer Center, the Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Huiling
authors.initials: H
authors.lastname: He
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bronisz
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yungui
authors.initials: Y
authors.lastname: Huang
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Dorota
authors.initials: D
authors.lastname: Kula
authors.forename: Anna
authors.initials: A
authors.lastname: Wojcicka
authors.forename: Nikhil
authors.initials: N
authors.lastname: Sebastian
authors.forename: Bernard
authors.initials: B
authors.lastname: Wen
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Puch
authors.forename: Michal
authors.initials: M
authors.lastname: Kalemba
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Stachlewska
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Czetwertynska
authors.forename: Joanna
authors.initials: J
authors.lastname: Dlugosinska
authors.forename: Kinga
authors.initials: K
authors.lastname: Dymecka
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
authors.forename: Marek
authors.initials: M
authors.lastname: Krawczyk
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morrison
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Richard T
authors.initials: RT
authors.lastname: Kloos
authors.forename: Krystian
authors.initials: K
authors.lastname: Jazdzewski
authors.forename: David E
authors.initials: DE
authors.lastname: Symer
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Vieland
authors.forename: Michael
authors.initials: M
authors.lastname: Ostrowski
authors.forename: Barbara
authors.initials: B
authors.lastname: Jarząb
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004789:Enzyme Activation; D005192:Family Health; D005260:Female; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020125:Mutation, Missense; D009820:Ohio; D010375:Pedigree; D011044:Poland; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins; C582067:SRGAP1 protein, human; D020764:cdc42 GTP-Binding Protein
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