Edery P, Eng C, Munnich A, Lyonnet S
Service de Génétique Médicale et Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-393, Hôpital Necker-Enfants Malades, Paris, France.
Bioessays. 1997 May;19(5):389-95. doi: 10.1002/bies.950190506.
Hirschsprung disease and the multiple endocrine neoplasia type 2 syndromes are hereditary disorders related to the abnormal migration, proliferation or survival of neural crest cells and their derivatives. Hirschsprung disease is a frequent disorder of the enteric nervous system, resulting in intestinal obstruction. The multiple endocrine neoplasia type 2 syndromes predispose to cancers of neural crest derivatives. Both diseases are associated with heterozygous mutations in the RET proto-oncogene. RET encodes a transmembrane receptor tyrosine kinase expressed in neural crest lineages and whose ligand, glial-cell-line-derived neurotrophic factor, has been very recently identified. In vitro expression studies demonstrate that while Hirschsprung disease mutations result in loss of function of the mutant RET tyrosine kinase, multiple endocrine neoplasia type 2 mutations lead to its constitutive activation. Thus, the two 'faces' of RET, gain of function and loss of function, each lead to a different syndrome, respectively: multiple endocrine neoplasia type 2, a cancer syndrome, or Hirschsprung disease, a developmental defect.
先天性巨结肠症和2型多发性内分泌肿瘤综合征是与神经嵴细胞及其衍生物的异常迁移、增殖或存活相关的遗传性疾病。先天性巨结肠症是一种常见的肠神经系统疾病，可导致肠梗阻。2型多发性内分泌肿瘤综合征易患神经嵴衍生物的癌症。这两种疾病都与RET原癌基因的杂合突变有关。RET编码一种在神经嵴谱系中表达的跨膜受体酪氨酸激酶，其配体——胶质细胞源性神经营养因子，最近才被确定。体外表达研究表明，虽然先天性巨结肠症突变导致突变型RET酪氨酸激酶功能丧失，但2型多发性内分泌肿瘤综合征突变导致其组成性激活。因此，RET的两种“面貌”，即功能获得和功能丧失，分别导致了不同的综合征：2型多发性内分泌肿瘤综合征，一种癌症综合征，或先天性巨结肠症，一种发育缺陷。
