The phenotypes associated with ret mutations in the multiple endocrine neoplasia type 2 syndrome.

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.