Ret protooncogene mutations and endocrine neoplasia--a story intertwined with neural crest differentiation.

Abstract

Germline mutations of the ret protooncogene were identified in patients with multiple endocrine neoplasia type 2A (MEN 2A) in 1993 (1, 2), a successful conclusion to a decade long mapping effort to identify the causative gene. Workers subsequently identified germline mutations of ret in MEN 28 (3,4) and somatic mutations in 25-50% of sporadic medullary thyroid carcinomas (MTC) (3). The ret gene encodes a tyrosine kinase receptor with 21 exons. The mutations in MEN 2A and familial MTC occur in a cysteine-rich extracellular region and mutate one of five conserved cysteines at codons 609, 611, 618, 620, or 634 in exons 10 and 11. Mutations of codon 634 are most commonly associated with classical MEN 2A, the association of MTC, pheochromocytoma, and parathyroid neoplasia. Multiple endocrine neoplasia type 2B, a syndrome characterized by MTC, pheochromocytoma, and mucosal neuromas, is caused by a point mutation in the substrate recognition pocket of the tyrosine kinase catalytic core at codon 918. Together, mutations of these six codons cause approximately 90-95% of hereditary MTC (5, 6). In a parallel series of investigations, a gene for hereditary Hirschsprung’s disease was mapped to the same locus, and inactivating mutations of ret were identified in a high percentage of familial Hirschsprung’s disease, a disorder characterized by a segmental loss of enteric neuronal innervation (7, 8). In yet another surprise, targeted disruption of