A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland.
Glucocorticoids produced in the adrenal cortex under the control of the hypothalamic-pituitary axis play a vital role in the maintenance of basal and stress-related homeostasis and influence health and well-being. To identify loci affecting regulation of the hypothalamic-pituitary-adrenal (HPA) axis...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3445511?pdf=render |
| _version_ | 1818312102248448000 |
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| author | Eduard Murani Henry Reyer Siriluck Ponsuksili Stephan Fritschka Klaus Wimmers |
| author_facet | Eduard Murani Henry Reyer Siriluck Ponsuksili Stephan Fritschka Klaus Wimmers |
| author_sort | Eduard Murani |
| collection | DOAJ |
| description | Glucocorticoids produced in the adrenal cortex under the control of the hypothalamic-pituitary axis play a vital role in the maintenance of basal and stress-related homeostasis and influence health and well-being. To identify loci affecting regulation of the hypothalamic-pituitary-adrenal (HPA) axis in the pig we performed a genome-wide association study for two parameters of acute and long-term adrenal activity: plasma cortisol level and adrenal weight. We detected a major quantitative trait locus at the position of the glucocorticoid receptor gene (NR3C1) - a key regulator of HPA axis activity. To determine the causal variant(s), we resequenced the coding region of NR3C1 and found three missense single nucleotide polymorphisms (SNPs). SNP c.1829C>T, leading to a p.Ala610Val substitution in the ligand binding domain, showed large (about 0.6× and 1.2× phenotypic standard deviations for cortisol level and adrenal weight, respectively), and highly significant (2.1E-39≤log10(1/p)≤1.7E+0) negative effects on both traits. We were able to replicate the association in three commercial pig populations with different breed origins. We analyzed effects of the p.Ala610Val substitution on glucocorticoid-induced transcriptional activity of porcine glucocorticoid receptor (GR) in vitro and determined that the substitution introduced by SNP c.1829C>T increased sensitivity of GR by about two-fold. Finally, we found that non-coding polymorphisms in linkage disequilibrium with SNP c.1829C>T have only a minor effect on the expression of NR3C1 in tissues related to the HPA axis. Our findings provide compelling evidence that SNP c.1829C>T in porcine NR3C1 is a gain-of-function mutation with a major effect on the activity of the adrenal gland. Pigs carrying this SNP could provide a new animal model to study neurobiological and physiological consequences of genetically based GR hypersensitivity and adrenal hypofunction. |
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| format | Article |
| id | doaj.art-3e3e3721073647aba6d1b1cdfa08ce3d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T08:12:31Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-3e3e3721073647aba6d1b1cdfa08ce3d2022-12-21T23:54:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0179e4551810.1371/journal.pone.0045518A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland.Eduard MuraniHenry ReyerSiriluck PonsuksiliStephan FritschkaKlaus WimmersGlucocorticoids produced in the adrenal cortex under the control of the hypothalamic-pituitary axis play a vital role in the maintenance of basal and stress-related homeostasis and influence health and well-being. To identify loci affecting regulation of the hypothalamic-pituitary-adrenal (HPA) axis in the pig we performed a genome-wide association study for two parameters of acute and long-term adrenal activity: plasma cortisol level and adrenal weight. We detected a major quantitative trait locus at the position of the glucocorticoid receptor gene (NR3C1) - a key regulator of HPA axis activity. To determine the causal variant(s), we resequenced the coding region of NR3C1 and found three missense single nucleotide polymorphisms (SNPs). SNP c.1829C>T, leading to a p.Ala610Val substitution in the ligand binding domain, showed large (about 0.6× and 1.2× phenotypic standard deviations for cortisol level and adrenal weight, respectively), and highly significant (2.1E-39≤log10(1/p)≤1.7E+0) negative effects on both traits. We were able to replicate the association in three commercial pig populations with different breed origins. We analyzed effects of the p.Ala610Val substitution on glucocorticoid-induced transcriptional activity of porcine glucocorticoid receptor (GR) in vitro and determined that the substitution introduced by SNP c.1829C>T increased sensitivity of GR by about two-fold. Finally, we found that non-coding polymorphisms in linkage disequilibrium with SNP c.1829C>T have only a minor effect on the expression of NR3C1 in tissues related to the HPA axis. Our findings provide compelling evidence that SNP c.1829C>T in porcine NR3C1 is a gain-of-function mutation with a major effect on the activity of the adrenal gland. Pigs carrying this SNP could provide a new animal model to study neurobiological and physiological consequences of genetically based GR hypersensitivity and adrenal hypofunction.http://europepmc.org/articles/PMC3445511?pdf=render |
| spellingShingle | Eduard Murani Henry Reyer Siriluck Ponsuksili Stephan Fritschka Klaus Wimmers A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland. PLoS ONE |
| title | A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland. |
| title_full | A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland. |
| title_fullStr | A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland. |
| title_full_unstemmed | A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland. |
| title_short | A substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland. |
| title_sort | substitution in the ligand binding domain of the porcine glucocorticoid receptor affects activity of the adrenal gland |
| url | http://europepmc.org/articles/PMC3445511?pdf=render |
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