SHORT REPORTSFamilial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor
Abstract
Familial glucocorticoid deficiency is an uncommon disorder that appears to be due to congenital insensitivity or resistance to adrenocorticotropin (ACTH), and is usually inherited in an autosomal recessive pattern. We investigated the DNA base sequence in a family with this condition by polymerase chain reaction amplification of DNA with pairs of primers that span the ACTH-receptor domain. The affected male proband showed a single base mutation, ser74→ile, in the sequence coding for the second transmembrane domain of the ACTH receptor. A similar defect was found in an affected sister, a normal sequence in an unaffected brother, and both alleles in each parent. This is only the second clinical disorder associated with a GTP-binding-protein-linked hormone-receptor mutation.
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Cited by (242)
A novel mutation in the NNT gene causing familial glucocorticoid deficiency, with a literature review
2024, Annales d'EndocrinologieFamilial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by low cortisol levels despite elevated adrenocorticotropin (ACTH). Mineralocorticoid secretion is classically normal. Clinical manifestations are secondary to low cortisol levels (recurrent hypoglycemia, chronic asthenia, failure to thrive, seizures) and high levels of ACTH (cutaneous-mucosal hyperpigmentation). FGD is often caused by mutations in the ACTH melanocortin 2 receptor gene (MC2R, 18p11.21, FGD type 1) or melanocortin receptor 2 accessory protein gene (MRAP, 21q22.11, FGD type 2). But mutations have also been described in other genes: the steroidogenic acute regulatory protein (STAR, 8q11.2q13.2, FGD type 3), nicotinamide nucleotide transhydrogenase (NNT, 5p12, FGD type 4) and thioredoxin reductase 2 genes (TXNRD2, 22q11.21, FGD type 5). We report the case of a 3-year-old boy recently diagnosed with FGD type 4 due to a novel mutation in NNT gene. A homozygous variant in exon 18 of the NNT gene, NM_012343.3:c.2764C>T, p.(Arg922*), determines a stop codon and, consequently, a non-functional truncated protein or absence of protein due to the nonsense-mediated decay (NMD) mechanism. We review the recent literature on NNT mutations and clinical presentations, which are broader than suspected. This disorder can result in significant morbidity and is potentially fatal if untreated. Precise diagnosis allows correct treatment and follow-up.
Animal models of adrenal genetic disorders
2023, Genetic Steroid Disorders: Second EditionAdrenal disorders that are caused by specific genetic alterations comprise a heterogeneous group of diseases with mostly low incidence that can affect patients from birth to adulthood. These conditions include failure of proper adrenal development resulting in adrenal agenesis or, conversely, adrenal tumorigenesis. Furthermore, deficiencies of adrenal steroidogenesis result in a lack or a shift of adrenal steroid production that can cause a specific clinical phenotype. For functional studies of gene products, mouse models remain to be intensively utilized as an experimental system owing to the similarity to humans with respect to genome organization, development, and physiology. For the majority of adrenal genetic disorders, mouse models exist that in most instances resemble the clinical phenotype observed in affected patients. Here we provide an overview of these models that allows for both mechanistic and therapeutically relevant investigations that will eventually translate into improved patient care.
Adrenal development
2023, Genetic Steroid Disorders: Second EditionThe adrenal gland (cortex) arises from the intermediate mesoderm in early embryonic life and develops during the fetal period to result in a mature organ capable of regulating homeostasis through the release of steroid hormones (e.g., mineralocorticoids, glucocorticoids, androgens). The adrenal medulla arises from neural crest cells and produces epinephrine/norepinephrine needed for an acute stress response. In this chapter, we discuss the mechanisms of adrenal development and provide an overview of some of the known regulatory factors that are currently thought to be involved in fetal adrenal growth and differentiation. We then provide an overview of current genetic causes of adrenal hypoplasia that can cause adrenal insufficiency in humans and explain how these conditions provide insight into adrenal development and as well as having implications for clinical management.
GPCR’s and Endocrinology
2022, Comprehensive PharmacologyG-protein-coupled receptors (GPCRs) form the largest family of receptors in humans, with over 800 members. These receptors mediate the effects of many hormones and convey numerous endocrine functions including growth, appetite regulation, bone development, glucose homeostasis and reproduction. Consequently, mutations in these receptors cause a spectrum of disorders and studies of these diseases has provided new insights into GPCR functions. This has led to an enhanced appreciation of the complexity of GPCR signaling achieved, in part, by the ability of receptors to couple to multiple G-protein pathways, utilization of sophisticated spatiotemporal signaling from plasma membrane and intracellular compartments, oligomerization of receptors and activation of G-protein-independent pathways. Pharmacological strategies for targeting GPCRs have become increasingly nuanced with the development of chimeric ligands targeting multiple receptors and the emergence of compounds that enable biased signaling. Future therapeutic approaches are likely to further enhance tissue and functional specificity. This article focusses on GPCRs involved in energy metabolism and growth (melanocortin, ghrelin, somatostatin, GLP-1 and GIP receptors); calcium homeostasis and skeletal development (calcium-sensing and parathyroid hormone receptors); thyroid function (TSH receptor); and reproduction (GnRHR, LHR, FSHR, KISS1R). Mutations in these GPCRs contribute to diverse human disorders including severe obesity, hyper/hypocalcaemia, skeletal dysplasia, hyper/hypothyroidism, precocious puberty, and delayed sexual development, and many are targets for currently approved drugs. For each receptor an understanding of the biological function, signal transduction mechanisms and pathophysiological consequences of human mutations will be explained, and current and future therapeutic strategies for targeting each receptor described.
Adrenocorticotrophin
2022, The PituitaryAdrenocorticotrophin (ACTH) is the anterior pituitary mediator of the hypothalamic–pituitary–adrenal axis that regulates the body's responses to a variety of stressors, particularly hypoglycemia, psychological stressors such as fear, and physical stressors such as hypovolemia. ACTH is the 39 amino acid product of proopiomelanocortin (POMC), which is principally synthesized in anterior pituitary corticotrophs, neurons of the mediobasal hypothalamus, and skin melanocytes. In each of these cell types, POMC is processed to a variety of melanocortins: ACTH (in the pituitary), α-MSH (in the skin and hypothalamus), and β-endorphin (in all three). ACTH, in response to hypothalamic corticotrophin–releasing hormone, is secreted and binds to the adrenal melanocortin 2 receptor (MC2R), a G protein–coupled receptor that signals through cyclic AMP to stimulate cortisol production and secretion. The main action of cortisol is to maintain adequate body fuel supplies and blood pressure during times of stress. α-MSH in skin, in response to ultraviolet light exposure, is released and binds to MC1R, which stimulates the production of melanin to increase skin pigmentation. α-MSH in the hypothalamus, in response to leptin, is released from neurons to act through MC4R receptors in the paraventricular nucleus of the hypothalamus, to decrease appetite and increase energy expenditure. Diseases involving ACTH are due to pituitary or ectopic tumors that secrete excessive ACTH, faulty transcription of the POMC gene, abnormal cleavage of the POMC precursor, or defects in signaling of POMC products via (at least) MC1R, MC2R, or MC4R. In addition, MC2R and MC4R require an accessory protein for their function, namely, melanocortin receptor 2 accessory protein (MRAP), and MRAP2, respectively, and mutations in these proteins impair the function of their associated receptors.
Adrenal cortex development and related disorders leading to adrenal insufficiency
2021, Molecular and Cellular EndocrinologyThe adult human adrenal cortex produces steroid hormones that are crucial for life, supporting immune response, glucose homeostasis, salt balance and sexual maturation. It consists of three histologically distinct and functionally specialized zones. The fetal adrenal forms from mesodermal material and produces predominantly adrenal C19 steroids from its fetal zone, which involutes after birth. Transition to the adult cortex occurs immediately after birth for the formation of the zona glomerulosa and fasciculata for aldosterone and cortisol production and continues through infancy until the zona reticularis for adrenal androgen production is formed with adrenarche. The development of this indispensable organ is complex and not fully understood. This article gives an overview of recent knowledge gained of adrenal biology from two perspectives: one, from basic science studying adrenal development, zonation and homeostasis; and two, from adrenal disorders identified in persons manifesting with various isolated or syndromic forms of primary adrenal insufficiency.