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ACTH Receptor

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Martin Reincke – One of the best experts on this subject based on the ideXlab platform.

  • Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH Receptor gene expression.
    European Journal of Endocrinology, 2005
    Co-Authors: Oliver Zwermann, Felix Beuschlein, Albrecht Klink, Enzo Lalli, Paolo Sassone-corsi, Martin Reincke

    BACKGROUND: The ACTH Receptor (ACTH-R) is a member of the seven transmembrane domain Receptor super-family. In non-functional adrenal adenomas and adrenocortical carcinomas, ACTH-R expression is low. However, no inhibitory factor for ACTH-R expression has been defined to date. DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene-1) is a general repressor of steroid production, inhibiting steroidogenic factor-1 (SF-1)-dependent expression of multiple steroidogenic enzymes. The aim of this study was to investigate whether ACTH-R gene transcription is affected by DAX-1 and whether this mechanism is involved in down-regulation of ACTH-R expression in adrenocortical tumors. METHODS: We screened 22 adrenocortical tumors for ACTH-R and DAX-1 mRNA expression by Northern blot. For in vitro analyses we co-transfected mouse Y1 adrenocortical carcinoma cells with the luciferase reporter gene vector pGL3 containing full-length constructs of human (h) or mouse (m) ACTH-R promoter together with a DAX-1 expression plasmid. These experiments were also performed using ACTH-R promoter 5′-deletion constructs and constructs mutated at the SF-1-binding sites. RESULTS: We found a negative correlation between DAX-1 and ACTH-R mRNA expression (R=-0.47, P

  • The –2 basepair initiation start site ACTH Receptor polymorphism influences ACTH induced adrenal androgen secretion
    Experimental and Clinical Endocrinology & Diabetes, 2005
    Co-Authors: Nicole Reisch, Marc Slawik, Oliver Zwermann, F Beuschlein, Martin Reincke

    Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the most abundant steroids in human circulation. Adrenocorticotropic hormone (ACTH) is the primary secretagogue stimulating adrenal androgens (AA) secretion. Yet, genetic and environmental factors are assumed to play a determinant role in the regulation of their biosynthesis and, thus, might explain the high variability of AA levels. We recently reported a polymorphism within the transcription initiation site of the ACTH Receptor promoter gene altering the consensus sequence from CTC to CCC at –2bp which results in lower promoter activity in vitro and is associated with impaired cortisol response to ACTH stimulation in vivo. Here we show that this polymorphism also affects ACTH dependent AA secretion. We studied 14 normal volunteers: 6 CCC/CCC carriers and 8 CTC/CTC carriers of the ACTH Receptor polymorphism. Baseline DHEA concentrations did not differ between groups. However, in a 6 hour ACTH stimulation test with increasing ACTH1–24 doses (120 to 3860 ng/mbody surface area/h), CCC/CCC carriers showed a significantly lower DHEA response compared to CTC/CTC carriers (area under the curve: 3201±358 vs. 5586±842µg/ml*min, P

  • Genetic influence of an ACTH Receptor promoter polymorphism on adrenal androgen secretion
    European journal of endocrinology, 2005
    Co-Authors: Nicole Reisch, Felix Beuschlein, Marc Slawik, Oliver Zwermann, Martin Reincke

    Objective: Adrenocorticotropic hormone (ACTH) is the primary secretagogue stimulating secretion of adrenal androgens (AA). Yet, genetic and environmental factors are assumed to play a determining role in the regulation of their biosynthesis and thus might explain the high variability of AA levels. Here we investigate the influence of an ACTH Receptor promoter polymorphism affecting ACTH Receptor gene transcription on ACTH-dependent dehydroepiandrosterone (DHEA) secretion. Design: We recently reported a polymorphism within the transcription initiation site of the ACTH Receptor gene promoter that alters the consensus sequence from CTC to CCC at 22bp. This results in lower promoter activity in vitro and is associated with impaired cortisol response to ACTH stimulation in vivo. We now studied 14 normal, lean volunteers aged 20‐35 years (eight CTC/CTC and six CCC/CCC carriers) in a 6-h ACTH stimulation test. Methods: After overnight dexamethasone suppression, ACTH1-24 was administered continuously in each subject with hourly increasing doses (120‐3840ng/m 2 body surface area/h) within a 6-h period. On a separate day, baseline DHEA samples were collected. Results: In the 6-h ACTH stimulation test, CTC/CTC carriers showed a significantly higher DHEA response than CCC/CCC carriers (area under the curve: 19367^2919 vs 11098^1241nmol/l per min; P , 0.04, Mann‐Whitney U-test). In contrast, baseline DHEA concentrations did not differ between groups. Conclusion: These data demonstrate that genetic variations within the ACTH Receptor promoter result in decreased DHEA secretion. Thus, we might have identified one of the genetic factors responsible for variation in ACTH-dependent DHEA secretion. European Journal of Endocrinology 153 711‐715

Martine Begeot – One of the best experts on this subject based on the ideXlab platform.

  • Compound heterozygosity of a frameshift mutation in the coding region and a single base substitution in the promoter of the ACTH Receptor gene in a family with isolated glucocorticoid deficiency.
    Journal of pediatric endocrinology & metabolism : JPEM, 2006
    Co-Authors: P. Tsiotra, Danielle Naville, Martine Begeot, Sotirios A. Raptis, Athina Koukourava, Valeria Kaltezioti, Mitchell E. Geffner, Constantine Tsigos

    Isolated glucocorticoid deficiency (IGD) is an autosomal recessive syndrome characterized by glucocorticoid insufficiency without mineralocorticoid deficiency. Mutations in the coding region of the ACTH Receptor (MC2R) have been reported in several families with IGD. We amplified and sequenced the entire MC2R coding region in a new family with IGD. The proband was found to be heterozygous (paternal allele) for the mutation Gly217fs, which changes the open reading frame of the MC2R protein resulting in a truncated Receptor. No other abnormality was found in the MC2R coding region. However, sequencing of the promoter region of the MC2R gene (-1017/44 bp) of the proband revealed a heterozygous T–>C substitution in the maternal allele at -2 bp position from initiation of the transcription start site. This substitution was found in only 6.5% in a healthy unrelated population. Constructs containing this polymorphism consistently showed a significant 15% decrease in promoter activity compared to wild type. In conclusion, we provide evidence that the IGD in this previously unreported family with ACTH resistance appears to be secondary to compound heterozygosity of a coding region and a promoter mutation in the MC2R gene.

  • Mutations in MRAP, encoding a new interacting partner of the ACTH Receptor, cause familial glucocorticoid deficiency type 2.
    Nature genetics, 2005
    Co-Authors: Louise A. Metherell, Danielle Naville, Martine Begeot, J. Paul Chapple, Sadani N. Cooray, Alessia David, Christian Becker, Franz Rüschendorf, Bernard Khoo, Peter Nürnberg

    Familial glucocorticoid deficiency (FGD), or hereditary unresponsiveness to adrenocorticotropin (ACTH; OMIM 202200), is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex, which stimulates glucocorticoid production. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood. Mutations of the ACTH Receptor (melanocortin 2 Receptor, MC2R) account for approximately 25% of cases of FGD. FGD without mutations of MC2R is called FGD type 2. Using SNP array genotyping, we mapped a locus involved in FGD type 2 to chromosome 21q22.1. We identified mutations in a gene encoding a 19-kDa single-transmembrane domain protein, now known as melanocortin 2 Receptor accessory protein (MRAP). We show that MRAP interacts with MC2R and may have a role in the trafficking of MC2R from the endoplasmic reticulum to the cell surface.

  • Exclusion of the Adrenocorticotropin (ACTH) Receptor (MC2R) Locus in Some Families with ACTH Resistance but No Mutations of the MC2R Coding Sequence (Familial Glucocorticoid Deficiency Type 2)
    The Journal of clinical endocrinology and metabolism, 1998
    Co-Authors: Danielle Naville, Adrian J L Clark, A. Weber, Philippe Durand, Emmanuelle Génin, Martine Begeot

    Several mutations in the coding exon of the ACTH Receptor (MC2R) gene have been reported in cases of familial glucocorticoid deficiency or FGD. However, many patients with a similar syndrome do not present any mutation in the coding region of this gene. This is the case in 11 families we have investigated. Patients in these families present the typical clinical features of FGD, but no mutation was found in the coding exon of the ACTH Receptor. To determine whether mutations on MC2R gene, but outside the coding region, may be involved in FGD in these families, we have performed a linkage analysis. Using three markers flanking MC2R gene on chromosome 18, we were able to exclude linkage in a region of 12 centimorgans around the gene. This result clearly indicates that FGD is genetically heterogeneous. Defects in gene(s) different from MC2R gene are implicated in this syndrome.

Adrian J L Clark – One of the best experts on this subject based on the ideXlab platform.

  • Stability and Turnover of the ACTH Receptor Complex.
    Frontiers in Endocrinology, 2019
    Co-Authors: Adrian J L Clark, Li F Chan

    Glucocorticoid production in mammals is principally regulated by the action of the pituitary hormone adrenocorticotropin (ACTH) acting on its cognate membrane Receptor on the zona fasciculata cells of the adrenal cortex. The Receptor for ACTH consists of two essential components, a small seven transmembrane domain G protein-coupled Receptor of the melanocortin Receptor subgroup known as the melanocortin 2 Receptor (MC2R) and a small single transmembrane domain protein that adopts a antiparallel homodimeric form and which is known as the melanocortin 2 Receptor accessory protein (MRAP). MRAP is essential for the trafficking of the MC2R to the cell surface as well as being required for Receptor responsiveness to ACTH at physiological concentrations – probably by facilitating ACTH binding, but possibly also by supporting G protein interaction with the MC2R. A number of studies have shown that ACTH stimulates the expression of functional Receptor at the cell surface and the transcription of both MC2R and MRAP mRNA. However the time course of these transcriptional effects differs such that MRAP is expressed relatively rapidly whereas MC2R transcription responds much more slowly. Furthermore, recent data suggests that MRAP protein is turned over with a short half-life whereas MC2R has a significantly longer half-life. These findings imply that these two ACTH Receptor proteins have distinct trajectories and that it is likely that MRAP-independent MC2R is present at the cell surface. In such a situation newly transcribed and translated MRAP could enable the rapid recruitment of functional Receptor at the plasma membrane without the need for new MC2R translation. This may be advantageous in circumstances of significant stress in that the potentially complex and perhaps inefficient process of de novo MC2R translation, folding, post-translational modification and trafficking can be avoided.

  • Melanocortin 4 Receptor becomes an ACTH Receptor by coexpression of melanocortin Receptor accessory protein 2.
    Molecular endocrinology (Baltimore Md.), 2013
    Co-Authors: Maria Josep Agulleiro, Adrian J L Clark, Raúl Cortés, Begoña Fernández-durán, S. Navarro, Raúl Guillot, Eirini Meimaridou, José Miguel Cerdá-reverter

    Melanocortin 2 Receptor (MC2R) is the only canonical ACTH Receptor. Its functional expression requires the presence of an accessory protein, known as melanocortin Receptor 2 accessory protein 1 (MRAP1). The vertebrate genome exhibits a paralogue gene called MRAP2, which is duplicated in zebrafish (MRAP2a and MRAP2b), although its function remains unknown. In this paper, we demonstrate that MRAP2a enables MC4R, a canonical MSH Receptor, to be activated by ACTH with a similar sensitivity to that exhibited by MC2R. Both proteins physically interact and are coexpressed in the neurons of the preoptic area, a key region in the control of the energy balance and hypophyseal secretion in fish. ACTH injections inhibit food intake in wild-type zebrafish but not in fish lacking functional MC4R. Both MRAP1 and MRAP2a are hormonally regulated, suggesting that these proteins are substrates for feed-back regulatory pathways of melanocortin signaling. Fasting has no effect on the central expression of MRAP2a but stimulates MRAP2b expression. This protein interacts and is colocalized with MC4R in the tuberal hypothalamic neurons but has no effect on the pharmacologic profile of MC4R. However, MRPA2b is able to decrease basal reporter activity in cell lines expressing MC4R. It is plausible that MRAP2b decreases the constitutive activity of the MC4R during fasting periods, driving the animal toward a positive energy balance. Our data indicate that MRAP2s control the activity of MC4R, opening up new pathways for the regulation of melanocortin signaling and, by extension, for the regulation of the energy balance and obesity.

  • Homozygous nonsense and frameshift mutations of the ACTH Receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency.
    Clinical endocrinology, 2009
    Co-Authors: Li F Chan, Martin O. Savage, Louise A. Metherell, Heiko Krude, Colin Ball, Stephen M. P. O'riordan, Colm Costigan, Sally Ann Lynch, Paolo Cavarzere, Adrian J L Clark

    Summary Objective Familial glucocorticoid deficiency (FGD) is a rare auto- somal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH Receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of Receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification. Design Clinical review of patients with nonsense MC2R mutations. Patients Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations. Results Mild disturbances in the renin-angiotensin-aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement. Conclusion Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.