The RetC620R 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, Italia Bongarzone

Research output: Contribution to journalArticle

Abstract

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 RETC620R 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 RetC620R 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.

Original languageEnglish
Pages (from-to)1262-1275
Number of pages14
JournalAmerican Journal of Pathology
Volume168
Issue number4
DOIs
Publication statusPublished - Apr 2006

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Carniti, C., Belluco, S., Riccardi, E., Cranston, A. N., Mondellini, P., Ponder, B. A. J., Scanziani, E., Pierotti, M. A., & Bongarzone, I. (2006). The RetC620R mutation affects renal and enteric development in a mouse model of Hirschsprung's disease. American Journal of Pathology, 168(4), 1262-1275. https://doi.org/10.2353/ajpath.2006.050607