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      Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia

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          Abstract

          Objective

          Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency.

          Design

          Mutational analysis of MC2R by direct sequencing.

          Patients

          Children ( n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1).

          Results

          MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time.

          Conclusions

          MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosis.

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          Most cited references29

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          Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene.

          The triple A syndrome (MIM 231550) is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia and alacrima. The frequent association with a variety of neurological features may result in a severely disabling disease. We previously mapped the syndrome to a 6 cM interval on chromosome 12q13 and have now refined the critical region to 0 cM between KRT8 and D12S1651. Overlapping bacterial artificial chromosome (BAC) sequences of a high resolution BAC/P1-derived artificial chromosome (PAC) contig were screened for gene content and a novel gene encoding a 546 amino acid polypeptide was identified. In nine triple A syndrome patients eight different homozygous and compound heterozygous mutations were found in this gene, most of them leading to a truncated protein suggesting loss of function. RNA blotting experiments revealed marked expression in neuroendocrine and gastrointestinal structures, which are predominantly affected in triple A syndrome, supporting the hypothesis that mutations in this triple A syndrome gene (AAAS) are responsible for the disease. The predicted protein belongs to the family of WD repeat-containing proteins which exhibit a high degree of functional diversity including regulation of signal transduction, RNA processing and transcription.
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            Adrenocorticotropin insensitivity syndromes.

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              The regulation of aldosterone synthase expression.

              Aldosterone, the primary human mineralocorticoid, is a major regulator of intravascular volume and blood pressure. The capacity of the adrenal gland to produce aldosterone is controlled, in large part, by the regulated transcription of CYP11B2, the gene encoding aldosterone synthase. Aldosterone synthase is responsible for the conversion of 11-deoxycorticosterone to aldosterone and is expressed only within the zona glomerulosa of the adrenal cortex. The development of new systems for in vitro studies of expression has helped define molecular mechanisms that regulate this enzyme and thus the capacity of the adrenal gland to produce aldosterone. Both potassium and angiotensin II (ANG II) increase intracellular calcium levels, which regulate expression of CYP11B2 through transcription factors that interact with defined sites in the 5'-flanking region of the gene.
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                Author and article information

                Journal
                Clin Endocrinol (Oxf)
                cen
                Clinical Endocrinology
                Blackwell Publishing Ltd
                0300-0664
                1365-2265
                01 February 2007
                : 66
                : 2
                : 205-210
                Affiliations
                [* ]UCL Institute of Child Health & Department of Medicine, University College London London, UK
                []Department of Endocrinology, Barts and the London, Queen Mary, University of London West Smithfield, London, UK
                []Department of Paediatric Endocrinology, Hamad Medical Centre Doha, Qatar
                Author notes

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Grants: JCA holds a Wellcome Trust Clinician Scientist Fellowship (068061).

                Correspondence: Dr John C. Achermann, Biochemistry, Endocrinology & Metabolism, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Tel.: +44 20 79052614; Fax: +44 20 74046191; E-mail: j.achermann@ 123456ich.ucl.ac.uk
                Article
                10.1111/j.1365-2265.2006.02709.x
                1859977
                17223989
                cf99c246-a726-4074-9258-bedf84ee1523
                © 2006 The Authors Journal compilation © 2006 Blackwell Publishing Ltd
                History
                : 16 June 2006
                : 18 July 2006
                : 18 August 2006
                : 21 August 2006
                Categories
                Original Article

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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