MENX

Abstract

Multiple endocrine neoplasias (MEN) are a group of hereditary disorders characterized by tumors arising in more than one neuroendocrine tissue. There are two major forms which can occur in humans, MEN type 1 (MEN1) and MEN type 2 (MEN2). These syndromes are transmitted as autosomal dominant traits with high penetrance and have a different tumor spectrum. MEN1 and MEN2 are caused by germline mutations in the MEN1 and RET genes, respectively. Recently, a variant of the MEN syndromes was discovered in a rat colony and was named MENX since affected animals develop tumors with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Extensive genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, heterozygous germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized which is caused by mutations in p27. Altogether these studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here I review the phenotypic features and the genetics of the MENX rat syndrome. I briefly address the main functions of p27 and how they are affected by the MENX-associated mutation. Finally, I present examples of how this animal model might be exploited as a translational platform for preclinical studies of pituitary adenomas.