Borrego Salud, Wright Fred A, Fernández Raquel M, Williams Nita, López-Alonso Manuel, Davuluri Ramana, Antiñolo Guillermo, Eng Charis
Unidad de Genética Médica y Diagnóstico Prenatal, Hospitales Universitarios Virgen del Rocío, Sevilla, Spain.
Am J Hum Genet. 2003 Jan;72(1):88-100. doi: 10.1086/345466. Epub 2002 Dec 9.
Hirschsprung disease (HSCR) is a common congenital disorder characterized by aganglionosis of the gut. The seemingly unrelated multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. Yet, germline mutations in the RET proto-oncogene are associated with both MEN 2 and HSCR. In the former, gain-of-function mutations in a limited set of codons is found, whereas, in the latter, loss-of-function mutations are found. However, germline RET mutation is associated with only 3% of a population-based series of isolated HSCR, and little is known about susceptibility to sporadic MTC. We have found previously that specific haplotypes comprising RET coding single-nucleotide polymorphisms (SNPs) comprising exon 2 SNP A45A were strongly associated with HSCR, whereas haplotypes associated with exon 14 SNP S836S were associated with MTC. In this study, we describe three novel intron 1 SNPs, and, together with the coding SNP haplotypes, the data suggest the presence of distinct ancestral haplotypes for HSCR and sporadic MTC in linkage disequilibrium with a putative founding susceptibility locus/loci. The data are consistent with the presence of a very ancient, low-penetrance founder locus approximately 20-30 kb upstream of SNP A45A, but the failure of the SNPs to span the locus presents challenges in modeling mode of transmission or ancestry. We postulate that this founding locus is germane to both isolated HSCR and MTC but also that different mutations in this locus would predispose to one or the other.
先天性巨结肠症（HSCR）是一种常见的先天性疾病，其特征为肠道神经节缺失。看似无关的2型多发性内分泌肿瘤（MEN 2）是一种常染色体显性疾病，其特征为甲状腺髓样癌（MTC）、嗜铬细胞瘤和甲状旁腺功能亢进。然而，RET原癌基因的种系突变与MEN 2和HSCR均相关。在前者中，发现了一组有限密码子中的功能获得性突变，而在后者中，则发现了功能丧失性突变。然而，种系RET突变仅与基于人群的孤立性HSCR系列中的3%相关，而对于散发性MTC的易感性知之甚少。我们之前发现，包含RET编码单核苷酸多态性（SNP）（包括外显子2 SNP A45A）的特定单倍型与HSCR密切相关，而与外显子14 SNP S836S相关的单倍型与MTC相关。在本研究中，我们描述了三个新的内含子1 SNP，并且与编码SNP单倍型一起，数据表明存在与假定的起始易感基因座处于连锁不平衡状态的、针对HSCR和散发性MTC的不同祖先单倍型。数据与在SNP A45A上游约20 - 30 kb处存在一个非常古老、低外显率的起始基因座一致，但SNP未能跨越该基因座给传播模式或祖先建模带来了挑战。我们推测这个起始基因座与孤立性HSCR和MTC均相关，而且该基因座中的不同突变会使人易患其中一种疾病。
