RET RECEPTOR POLYMORPHISMS & HIRSCHSPRUNG DISEASE

描述(摘自研究人员摘要)：RET原癌基因， 编码一种受体酪氨酸激酶的基因，是 先天性巨结肠症(HSCR)是一种先天性肠神经节缺失， 多发性内分泌肿瘤2型(MENS 2)，一种遗传性癌症综合征和 神经官能症。男性2的特点是甲状腺髓样癌(MTC)， 嗜铬细胞瘤和甲状旁腺增生症。需要四个相关的配体来 在与RET结合之前，先与四个相关的辅受体结合。高透过率增益 功能突变导致男性2，功能突变丢失导致子集 HSCR(30-50%的家族性病例和3%的孤立病例)。最近， PIS在RET基因中发现了A45A和L769L两个多态性，这两个基因分别是 在小样本中与HSCR相关。相比之下，S836在 散发性MTC患者，尤其是携带M918T基因多态的患者 他们的肿瘤。基于这些初步的基因发现，PI假设 RET中常见的低外显性等位基因可以作为低水平 易患HSCR的易感基因。此外，他们还假设， 与HSCR相关的变异体在散发性MTC病例中的表达不足 反之亦然。为了检验这些假设，PI将积累大量的 以人群为基础的HSCR病例系列(n=250)和散发性MTC(n=200)至 确定RET中多态变异的频率，并确定其 单倍型。种族匹配、地区匹配的正常对照将与 病例：控制比例为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，传递不平衡 检验，并进行基于单倍型的连锁不平衡分析。这些方法 已用于高危人群和未受影响的父母的试点系列并发现 上游15kb的一个新的低外显度基因座的证据包括 45号密码子，可易感于大多数孤立的HSCR。PIS计划 扩大他们的调查范围以分离这个新的基因座并直接测试 这是HSCR扩展系列中的一个基因座。此外，编码该基因的 RET的配体和辅助受体同样是低外显性的良好候选者 易感基因。这些基因和类似基因的基因分型和单倍型 联合测试将在HSCR和MTC进行。最终发现变种 与疾病状态相关联的数据将在 转录本、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.