RGD Reference Report - Gain of function mutation in the mineralocorticoid receptor of the Brown Norway rat. - Rat Genome Database

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

Authors: Marissal-Arvy, N  Lombes, M  Petterson, J  Moisan, MP  Mormede, P 
Citation: Marissal-Arvy N, etal., J Biol Chem 2004 Sep 17;279(38):39232-9. Epub 2004 Jul 12.
RGD ID: 1302889
Pubmed: PMID:15252022   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M407436200   (Journal Full-text)

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 pressure.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Gmadr1Ratadrenal gland disease  IAGP  RGD 
Bw28RatAdrenal Insufficiency  IAGP  RGD 
Bw29RatAdrenal Insufficiency  IAGP  RGD 
Foco1RatAdrenal Insufficiency  IAGP  RGD 
Foco2RatAdrenal Insufficiency  IAGP  RGD 
Gmadr1RatAdrenal Insufficiency  IAGP  RGD 
Salc1RatAdrenal Insufficiency  IAGP  RGD 
Salc2RatAdrenal Insufficiency  IAGP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Salc1Ratabnormal drinking behavior  QTM  RGD 
Salc2Ratabnormal drinking behavior  QTM  RGD 
Foco1Ratabnormal food intake  QTM  RGD 
Foco2Ratabnormal food intake  QTM  RGD 
Gmadr1Ratsmall adrenal glands  IAGP  RGD 
Bw28Ratweight loss  IDA  RGD 
Bw29Ratweight loss  IDA  RGD 
Objects Annotated

QTLs
Bw28  (Body weight QTL 28)
Bw29  (Body weight QTL 29)
Foco1  (Food consumption QTL 1)
Foco2  (Food consumption QTL 2)
Gmadr1  (Adrenal mass QTL 1)
Salc1  (Saline consumption QTL 1)
Salc2  (Saline consumption QTL 2)

Strains
BN/OrlIcoCrlf  (NA)
F344/IcoCrlf  (NA)

Objects referenced in this article
Strain F344 Fischer Rattus norvegicus
Gene Nr3c2 nuclear receptor subfamily 3, group C, member 2 Rattus norvegicus

Additional Information