Gain of function mutation in the mineralocorticoid receptor of the Brown Norway rat.
J. Biol. Chem.. 2004-07-12; 279(38): 39232-39239
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1. J Biol Chem. 2004 Sep 17;279(38):39232-9. Epub 2004 Jul 12.
Gain of function mutation in the mineralocorticoid receptor of the Brown Norway
Marissal-Arvy N(1), Lombès M, Petterson J, Moisan MP, Mormède P.
(1)Neurogénétique et Stress, Institut National de la Santé et de la Recherche
Médicale, Unité 471, Université de Bordeaux 2, France.
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
mineralocorticoid receptor by aldosterone, and surprisingly by progesterone as
well, which could substitute for aldosterone after adrenalectomy in Brown Norway
rats. We challenged this hypothesis in vivo and showed that plasma progesterone
is higher in Brown Norway male rats and partially compensates for aldosterone
after adrenalectomy. This work illustrates the interest of a pluristrategic
approach to explore the mineralocorticoid receptor signaling pathway and its
implication in the regulation of hydroelectrolytic homeostasis and blood
PMID: 15252022 [Indexed for MEDLINE]