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.
J Clin Endocrinol Metab. 2013 May;98(5):E973-80. doi: 10.1210/jc.2012-3823. Epub 2013 Mar 28.
Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative.
The objective of this study was to identify susceptibility genes for PTC.
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.
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.
Our findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type.
甲状腺乳头状癌（PTC）具有高度遗传性，但寻找易患基因的努力大多是阴性的。
本研究旨在鉴定 PTC 的易感基因。
对 38 个家族进行全基因组连锁分析。对 2 大 PTC 患者和对照组进行靶向关联研究和筛选。在功能研究中测试候选 DNA 变体。
连锁分析和关联研究将 Slit-Robo Rho GTPase 激活蛋白 1 基因（SRGAP1）鉴定为连锁峰中的候选基因。2 个错义变体 Q149H 和 A275T 分别定位于 Fes/CIP4 同源结构域中，与疾病分离。一个错义变体 R617C 位于 RhoGAP 结构域，存在于 1 个家族中。生化分析表明，CDC42 的失活能力，即 SRGAP1 的一个关键功能，严重受损由 Q149H 和 R617C 变体引起。
我们的研究结果表明，SRGAP1 是 PTC 易感性的候选基因。SRGAP1 可能是一种低外显率基因，可能是修饰类型。
