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(American Journal of Pathology. 2006;168:1262-1275.)
© 2006 American Society for Investigative Pathology

The Ret^C620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung’s Disease

Cristiana Carniti^*, Sara Belluco, Elena Riccardi, Aaron N. Cranston, Piera Mondellini^*, Bruce A.J. Ponder, Eugenio Scanziani, Marco A. Pierotti^* and Italia Bongarzone^*

From the Department of Experimental Oncology and Laboratories,^* Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; the Department of Animal Pathology, Igiene e Sanità Pubblica Veterinaria–Sezione di Anatomia Patologica Veterinaria e Patologia Aviare, Università degli Studi di Milano, Milan, Italy; Institute of Molecular Oncology, Fondazione Italiana per la Ricerca sul Cancro, Milan, Italy; and the Department of Oncology, the Cambridge Institute for Medical Research and Cancer Research United Kingdom, University of Cambridge, Cambridge, United Kingdom

In rare families RET tyrosine kinase receptor substitutions located in exon 10 (especially at positions 609, 618, and 620) can concomitantly cause the MEN 2A (multiple endocrine neoplasia type 2A) or FMTC (familial medullary thyroid carcinoma) cancer syndromes, and Hirschsprung’s disease (HSCR). No animal model mimicking the co-existence of the MEN 2 pathology and HSCR is available, and the association of these activating mutations with a developmental defect still represents an unresolved problem. The aim of this work was to investigate the significance of the RET^C620R substitution in the pathogenesis of both gain- and loss-of-function RET-associated diseases. We report the generation of a line of mice carrying the C620R mutation in the Ret gene. Although Ret^C620R homozygotes display severe defects in kidney organogenesis and enteric nervous system development leading to perinatal lethality. Ret^C620R heterozygotes recapitulate features characteristic of HSCR including hypoganglionosis of the gastrointestinal tract. Surprisingly, heterozygotes do not show any defects in the thyroid that might be attributable to a gain-of-function mutation. The Ret^C620R allele is responsible for HSCR and affects the development of kidneys and the enteric nervous system (ENS). These mice represent an interesting model for studying new therapeutic approaches for the treatment of HSCR disease.