Endocrine Abstracts

Background: We recently reported the first human mutation in mini-chromosome maintenance homologue 4 (MCM4) in a cohort of patients with adrenal failure. We now report the endocrine phenotype of 14 patients with MCM4 mutations.Methods: Patients case notes were examined and investigations performed to fully assess adrenal function, pubertal development, gonadal function and growth.Results: 13 of 14 patients have developed isolated g...

Background: The melanocortin 2 receptor (MC2R)/melanocortin 2 receptor accessory protein (MRAP) are critical components of the hypothalamo-pituitary-adrenal axis (HPA). MRAP2, homologue of MRAP, can also regulate the MC2R in vitro, however, the physiological significance of this is unclear. We studied the expression of the MRAPs and MC2R in a well-defined rat model of endotoxin induced septic shock. These animals have been shown to have higher ACTH and corticosterone le...

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by resistance to the action of ACTH leading to glucocorticoid deficiency with preserved mineralocorticoid and gonadal function. In 1993 we identified mutations in the ACTH receptor (melanocortin 2 receptor; MC2R), although these only explained around 25% of cases. More recently a traditional homozygosity mapping approach identified mutations in a novel gene which we named melan...

GHI is a genetic condition in which patients present with growth failure due to primary IGF1 deficiency caused by a defect in the GH-IGF1 axis. In the last 10 years in the Centre for Endocrinology of WHRI at Barts and the London, 24 causative mutations in genes of the GH–IGF1 axis have been determined in 58 patients (Table 1). STAT5B mutations were responsible in 2 cases, IGFALS in 4 but the majority of defects identified were in GHR. Most mutations identifi...

Background and aims: The melanocortin-2-receptor accessory protein (MRAP) is essential for melanocortin-2-receptor (MC2R) function through receptor trafficking and signalling, enabling adrenal glucocorticoid synthesis in response to ACTH stimulation. Disabling mutations of MRAP result in life-threatening glucocorticoid deficiency, known as familial glucocorticoid deficiency type 2. MRAP has a single paralogue in the human genome, MRAP2. In vitro MRAP2 has a similar acti...

Background: FGD is an autosomal recessive disorder causing glucocorticoid deficiency. Mutations in the ACTH receptor (MC2R) or the MC2R accessory protein (MRAP) cause FGD types 1 & 2 respectively. All the reported MRAP mutations result in abolition of a functional protein. This is reflected clinically as type 2 patients present early, no patient described to date has presented later than 1.6yrs. In contrast FGD type 1 mutations are usually missense and patients have a medi...

We recently demonstrated that fetal programming changes induced by a maternal low protein diet (MLP) that lead to the development of hypertension in the rat offspring were associated with increased expression of the AT1b angiotensin receptor (AT1b) and reduced methylation of its promoter in the adrenal gland. Previous findings have suggested that overactivity of the maternal pituitary–adrenal axis in pregnancy results in overexposure of the fetus to glucocorticoids which ...

Mutations in the ACTH receptor (Melanocortin 2 receptor/MC2R) are associated with Familial Glucocorticoid Deficiency/FGD. FGD is an autosomal recessive disorder that results from ACTH insensitivity at the adrenal cortex. However, only about 25% of FGD are caused by mutations in the MC2R suggesting the genetically heterogeneous nature of the disease. The transfection-mediated functional expression of the MC2R can only be achieved in cell lines of adrenal origin implying that th...

Familial glucocorticoid deficiency (FGD) results from the inability of the adrenal cortex to produce cortisol in response to ACTH stimulation and can be fatal if unrecognised. The disease manifests clinically with increased ACTH and reduced cortisol levels. Our group has recently demonstrated that oxidative stress is implicated in the pathogenesis of this disorder.We previously identified mutations in nicotinamide nucleotide transhydrogenase (NNT) in pat...

Introduction: In recent years a growing number of gene mutations have been identified which cause a myriad of syndromes having adrenal insufficiency as a core characteristic. The evolution of each syndrome is dependent on the variant and the particular gene affected. Common practice is for candidate genes to be sequenced individually, which can be time consuming and is complicated by overlapping clinical phenotypes. The increasing availability and cost effectiveness of whole e...