RET RECEPTOR POLYMORPHISMS & HIRSCHSPRUNG DISEASE

描述（改编自研究者摘要）：RET原癌基因， 编码受体酪氨酸激酶，是 先天性巨结肠症（HSCR），一种先天性肠神经节缺失， 多发性内分泌瘤2型（MEN 2），一种遗传性癌症综合征， 神经嵴病MEN 2的特征是甲状腺髓样癌（MTC）， 嗜铬细胞瘤和副甲状腺增生。需要四个相关配体来 在与RET结合之前与四种相关的辅助受体结合。高增益 功能突变导致MEN 2，功能缺失突变导致MEN 2的一个子集。 HSCR（30- 50%的家族性病例和3%的孤立病例）。近日 PI在RET基因内发现了2种多态性，A45 A和L769 L， 在小样本中与HSCR相关。相比之下，S836 S在 散发性MTC个体，特别是那些具有M918 T多态性的个体， 他们的肿瘤基于这些初步的遗传学发现，PI假设 RET中常见的低等位基因可以作为低水平的 易感HSCR的等位基因。此外，他们假设， 与HSCR相关的变异在散发的MTC病例中代表性不足 且反之亦然。为了验证这些假设，PI将累积大量 基于人群的HSCR病例（n=250）和散发性MTC（n=200）系列， 确定RET中多态性变体的频率，并确定其 单倍型。人种匹配、地区匹配的正常对照将与 病例：对照比例为1：3。这些数据将使用标准进行分析， 病例对照配对关联分析，传播不平衡 单倍型连锁不平衡分析。这些方法 已经在64个HSCR和未受影响的父母的试验系列中使用， 一个新的上游15 kb的低等位基因位点的证据，包括 密码子45，这可能倾向于大多数分离的HSCR。PI计划 扩展他们的研究，分离这个新的基因座， HSCR扩展序列中的这个位点。此外，编码这些蛋白的基因 RET的配体和共受体是同样好的候选者， 易感基因这些基因的基因分型和单倍型以及类似的 将在HSCR和MTC中进行关联测试。最后发现变种 与疾病状态相关的功能将在 转录物、蛋白质和细胞生物学水平。

DESCRIPTION (Adapted from investigator's abstract): The RET proto-oncogene, encoding a receptor tyrosine kinase, is the susceptibility gene for Hirschsprung disease (HSCR), a congenital absence of enteric ganglia, and for multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome and neurocristopathy. MEN 2 are characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and parathroid hyperplaisa. Four related ligands are needed to bind to four related coreceptors before binding to RET. High penetrance gain of function mutations cause MEN 2 and loss of function mutations cause a subset of HSCR (30-50 percent of familial and 3 percent of isolated cases). Recently, the PIs have found 2 polymorphisms, A45A and L769L within the RET gene that are associated with HSCR in small sample. In contrast S836S are over-represented in individuals with sporadic MTC, particularly those with M918T polymorphism in their tumors. Based on these preliminary genetic findings, the PIs hypothesize that common low penetrance alleles within RET can act as low level susceptibility alleles predisposing to HSCR. Further, they hypothesize that the variants associated with HSCR will be underrepresented in sporadic MTC cases and vice versa. To test these hypotheses, the PIs will accrue a large population-based series of HSCR cases (n=250) and sporadic MTC (n=200) to determine the frequency of polymorphic variants in RET and to determine their haplotypes. Race-matched, region-matched normal controls will be accrued with cases: control ratio of 1:3. These data will be analyzed using the standard case-control matched association analysis, the transmission-disequilibrium test, and the haplotype-based linkage disequilibrium analysis. These methods have been used on a pilot series of 64 HSCR and unaffected parents and found evidence for a novel low penetrance locus with 15kb upstream and including codon 45 which could predispose to the majority of isolated HSCR. The PIs plan to extend their investigations to isolate this new locus and to directly test this locus in the extended series of HSCR. Further, the genes encoding the ligands and coreceptors of RET are equally good candidates for low penetrance susceptibility genes. Genotyping and haplotyping of these genes and similar tests of association will be performed in HSCR and MTC. Finally variants found to be associated with disease status will be tested functionally at the transcript, protein and cell biological level.