Ponder B A
Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, United Kingdom.
Cancer Res. 1999 Apr 1;59(7 Suppl):1736s-1741s; discussion 1742s.
Different specific mutations in the ret tyrosine kinase give rise to different clinical types of the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). The explanation for these genotype-phenotype correlations is not yet certain. Several lines of evidence suggest that they result either from different levels of RET activation induced by different mutations or, in one class of mutation, possibly from altered substrate specificity of the RET tyrosine kinase. ret is expressed during development in a lineage of neuroectodermal cells that gives rise to the thyroid C cells and the adrenal medulla, which are involved in tumor formation in MEN 2. ret is also expressed in the enteric autonomic nervous system. Inactivating mutations of ret lead to Hirschsprung's disease, a congenital absence or maldevelopment of the enteric plexuses, whereas activating mutations in one variety of the MEN 2 syndrome lead to their overgrowth. The range of phenotypic expression seen in families with different ret mutations and the variation within families with the same mutation provide a potentially interesting and tractable system for the analysis of both the relationship between phenotype and genotype and the effects of modifier genes.
RET酪氨酸激酶中的不同特定突变会引发遗传性癌症综合征2型多发性内分泌腺瘤病（MEN 2）的不同临床类型。这些基因型与表型相关性的解释尚不确定。几条证据表明，它们要么是由不同突变诱导的不同水平的RET激活导致的，要么在一类突变中，可能是由RET酪氨酸激酶改变的底物特异性导致的。RET在发育过程中在神经外胚层细胞谱系中表达，该谱系产生甲状腺C细胞和肾上腺髓质，它们参与MEN 2中的肿瘤形成。RET也在肠自主神经系统中表达。RET的失活突变会导致先天性巨结肠，即肠神经丛先天性缺失或发育不良，而MEN 2综合征的一种变体中的激活突变会导致它们过度生长。在具有不同RET突变的家族中观察到的表型表达范围以及具有相同突变的家族内部的变异，为分析表型与基因型之间的关系以及修饰基因的作用提供了一个潜在有趣且易于处理的系统。
