+1 Recommend
1 collections
      • Record: found
      • Abstract: found
      • Article: found

      Isolated Addison's disease is unlikely to be caused by mutations in MC2R, MRAP or STAR, three genes responsible for familial glucocorticoid deficiency


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.



          Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease caused by ACTH resistance and leads to isolated glucocorticoid deficiency. Although FGD patients typically have normal mineralocorticoid secretion, subtle alterations in the renin–angiotensin–aldosterone axis have been reported in a subset of patients at presentation. Anecdotally, some patients with FGD have been initially diagnosed as having Addison's disease (AD), with implications for treatment and genetic counselling. Currently, mutations in three genes: the ACTH receptor ( MC2R); the melanocortin 2 receptor accessory protein ( MRAP); and the steroidogenic acute regulatory protein ( STAR) are known to give rise to FGD types 1–3. We investigated a cohort of autoantibody-negative AD patients for mutations in these genes.


          Forty patients with known AD without evidence of autoimmune disease were screened for mutations in MC2R, MRAP and STAR. In addition, patients were genotyped for the MC2R promoter polymorphism previously associated with reduced responsiveness to ACTH.


          No mutations in MC2R, MRAP or STAR were identified in any patient. The frequencies of the MC2R promoter polymorphism were similar to those reported in healthy controls.


          FGD does not appear to be underdiagnosed in the AD population. However, in ∼50% of patients with FGD, no genetic cause has yet been identified and it is possible that the other, as yet unidentified, genes giving rise to FGD may be implicated in AD.

          Related collections

          Most cited references15

          • Record: found
          • Abstract: found
          • Article: not found

          Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency.

          Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia and/or overwhelming infection. Mutations of the ACTH receptor (MC2R) and the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 and 2 respectively, account for approximately 45% of cases. A locus on chromosome 8 has previously been linked to the disease in three families, but no underlying gene defect has to date been identified. The study design comprised single-nucleotide polymorphism genotyping and mutation detection. The study was conducted at secondary and tertiary referral centers. Eighty probands from families referred for investigation of the genetic cause of FGD participated in the study. There were no interventions. Analysis by single-nucleotide polymorphism array of the genotype of one individual with FGD previously linked to chromosome 8 revealed a large region of homozygosity encompassing the steroidogenic acute regulatory protein gene, STAR. We identified homozygous STAR mutations in this patient and his affected siblings. Screening of our total FGD patient cohort revealed homozygous STAR mutations in a further nine individuals from four other families. Mutations in STAR usually cause lipoid congenital adrenal hyperplasia, a disorder characterized by both gonadal and adrenal steroid deficiency. Our results demonstrate that certain mutations in STAR (R192C and the previously reported R188C) can present with a phenotype indistinguishable from that seen in FGD.
            • Record: found
            • Abstract: found
            • Article: not found

            Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia.

            Lipoid congenital adrenal hyperplasia is a severe disorder of adrenal and gonadal steroidogenesis caused by mutations in the steroidogenic acute regulatory protein (StAR). Affected children typically present with life-threatening adrenal insufficiency in early infancy due to a failure of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) biosynthesis, and 46,XY genetic males have complete lack of androgenization and appear phenotypically female due to impaired testicular androgen secretion in utero. The objective of this study was to investigate whether nonclassic forms of this condition exist. Sequence analysis of the gene encoding StAR was undertaken in three children from two families who presented with primary adrenal insufficiency at 2-4 yr of age; the males had normal genital development. Identified mutants were tested in a series of biochemical assays. DNA sequencing identified homozygous StAR mutations Val187Met and Arg188Cys in these two families. Functional studies of StAR activity in cells and in vitro and cholesterol-binding assays showed these mutants retained approximately 20% of wild-type activity. These patients define a new disorder, nonclassic lipoid congenital adrenal hyperplasia, and represent a new cause of nonautoimmune Addison disease (primary adrenal failure).
              • Record: found
              • Abstract: found
              • Article: not found

              Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis.

              ACTH (i.e., corticotropin) is the principal regulator of the hypothalamus-pituitary-adrenal axis and stimulates steroidogenesis in the adrenal gland via the specific cell-surface melanocortin 2 receptor (MC2R). Here, we generated mice with an inactivation mutation of the MC2R gene to elucidate the roles of MC2R in adrenal development, steroidogenesis, and carbohydrate metabolism. These mice, the last of the knockout (KO) mice to be generated for melanocortin family receptors, provide the opportunity to compare the phenotype of proopiomelanocortin KO mice with that of MC1R-MC5R KO mice. We found that the MC2R KO mutation led to neonatal lethality in three-quarters of the mice, possibly as a result of hypoglycemia. Those surviving to adulthood exhibited macroscopically detectable adrenal glands with markedly atrophied zona fasciculata, whereas the zona glomerulosa and the medulla remained fairly intact. Mutations of MC2R have been reported to be responsible for 25% of familial glucocorticoid deficiency (FGD) cases. Adult MC2R KO mice resembled FGD patients in several aspects, such as undetectable levels of corticosterone despite high levels of ACTH, unresponsiveness to ACTH, and hypoglycemia after prolonged (36 h) fasting. However, MC2R KO mice differ from patients with MC2R-null mutations in several aspects, such as low aldosterone levels and unaltered body length. These results indicate that MC2R is required for postnatal adrenal development and adrenal steroidogenesis and that MC2R KO mice provide a useful animal model by which to study FGD.

                Author and article information

                Eur J Endocrinol
                European Journal of Endocrinology
                BioScientifica (Bristol )
                February 2010
                : 162
                : 2
                : 357-359
                [1 ]simpleBarts and the London School of Medicine and Dentistry, Centre for Endocrinology, John Vane Science Centre simpleQueen Mary University of London Charterhouse Square, London, EC1M 6BQUK
                [2 ]simpleInstitute of Human Genetics, Centre for Life simpleNewcastle University Central Parkway, Newcastle upon Tyne, NE1 3BZUK
                Author notes
                (Correspondence should be addressed to A J L Clark; a.j.clark@ 123456qmul.ac.uk )
                © 2010 European Society of Endocrinology

                This is an Open Access article distributed under the terms of the European Journal of Endocrinology's Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 15 October 2009
                : 19 October 2009
                Funded by: Medical Research Council
                Clinical Study

                Endocrinology & Diabetes
                Endocrinology & Diabetes


                Comment on this article