Gain of function mutation in the mineralocorticoid receptor of the Brown Norway rat.

The Journal of Biological Chemistry
N Marissal-ArvyP Mormède

Abstract

The aim of this research was to identify the molecular bases of differences in sensitivity to corticosteroid hormones between Brown Norway and Fischer 344 rats. We previously showed an apparent insensitivity to adrenalectomy in Brown Norway rats. Based on our first hypothesis of a different activity/reactivity of the mineralocorticoid signaling pathway between the two rat strains, we sequenced Brown Norway and Fischer 344 mineralocorticoid receptor cDNA and identified a tyrosine to cysteine substitution (Y73C) in the N-terminal part of the Brown Norway mineralocorticoid receptor. As a first step, this substitution gave us a means to distinguish the Brown Norway allele from the Fischer 344 at the mineralocorticoid receptor locus in an F2 population. We showed a strong genetic linkage between the mineralocorticoid receptor genotype and sensitivity to adrenalectomy. A subsequent genome-wide linkage analysis confirmed the involvement of the mineralocorticoid receptor locus and implicated other loci, including one on chromosome 4, which collectively explain a large part of the strain differences in corticosteroid receptor responses. In vitro studies further revealed that the Y73C substitution induces greater transactivation of the m...Continue Reading

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Citations

Sep 10, 2005·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Bastien LlamasMarie-Pierre Moisan
Feb 25, 2011·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Domenico L Di Curzio, Daniel Goldowitz
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Sep 24, 2010·American Journal of Physiology. Renal Physiology·Nourdine FaresseOlivier Staub

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