Kusafuka T, Puri P
Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland.
Pediatr Surg Int. 1997;12(1):11-8. doi: 10.1007/BF01194794.
RET gene alterations as disease-causative mutations have been demonstrated in five different disease entities: Hirschsprung's disease (HD); papillary thyroid carcinoma; and three types of inherited cancer syndromes: multiple endocrine neoplasia (MEN) 2A, MEN 2B, and familial medullary thyroid carcinoma. RET is expressed during embryogenesis in a temporally and spatially regulated manner, and plays an important role in the normal development of a variety of cell lineages, particularly in the establishment of the enteric nervous system. RET mutations observed in patients with HD are scattered along the gene without any hot spots, and possess a loss-of-function effect. RET mutations are detected with a higher incidence among familial cases (50%) than sporadic cases (15%-20%), and are more closely associated with long-segment HD than short-segment disease. In contrast to HD mutations, missense mutations observed in MEN 2 syndromes occur at specific codons, and gene rearrangements are characteristic in papillary thyroid carcinoma. Both missense mutations and gene rearrangements act in a dominant fashion, and cause constitutive phosphorylation on the tyrosine of RET and highly enhance RET kinase activity, leading to transforming or oncogenic activity.
RET基因改变作为致病突变已在五种不同的疾病实体中得到证实：先天性巨结肠症（HD）；甲状腺乳头状癌；以及三种遗传性癌症综合征：多发性内分泌腺瘤（MEN）2A、MEN 2B和家族性甲状腺髓样癌。RET在胚胎发育过程中以时空调节的方式表达，并在多种细胞谱系的正常发育中发挥重要作用，特别是在肠神经系统的建立中。在HD患者中观察到的RET突变沿基因分散，没有任何热点，并且具有功能丧失效应。在家族性病例（50%）中检测到RET突变的发生率高于散发性病例（15%-20%），并且与长段HD的相关性比短段疾病更密切。与HD突变相反，在MEN 2综合征中观察到的错义突变发生在特定密码子处，并且基因重排在甲状腺乳头状癌中具有特征性。错义突变和基因重排均以显性方式起作用，并导致RET酪氨酸的组成型磷酸化并高度增强RET激酶活性，从而导致转化或致癌活性。
