Endocrine Abstracts

Triple A syndrome (also known as Allgrove’s syndrome, MIM #231550) is a rare autosomal recessive disorder characterised by ACTH-resistant adrenal insufficiency, alacrima and achalasia. Neurological features may also be present. Various combinations of these features may be present which evolve over time. Triple A syndrome is caused by mutations in the AAAS gene which encodes for the protein ALADIN, a member of the nuclear pore complex, whose function is incompletely under...

Mutations in CYP11A1, like those in STAR cause lipoid congenital adrenal hyperplasia manifesting with adrenal and gonadal insufficiencies along with derangements of the renin/angiotensin system. Increased adrenal size is usually a feature of STAR but not of CYP11A1 mutation. Milder forms presenting without all of these features have also been described. We present six patients from four families with CYP11A1 mutations discovered by ...

Congenital adrenal hyperplasia (CAH) summarizes a group of genetic disorders of enzymes involved in cortisol biosynthesis. The most common causes detrimental mutations in the steroidogenic cytochrome P450 enzyme 21-hydroxylase (CYP21A2). Patients are dependent on a lifelong oral cortisol replacement therapy to ensure survival but quality of life is often reduced and co-morbidities are substantially increased. Also, the administered supraphysiological glucocorticoid dosescannot...

The tumour suppressor menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, has been reported to be a component of the Wnt/β-catenin signalling pathway. To investigate the effects of menin loss on this pathway, we have determined the cDNA expression profiles of pituitary tumours from 5 Men1+/− mice and in normal pituitaries from 5 Men1+/+ littermates by extracting total RNA and by hybridizing it to Affymetrix Mous...

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of anterior pituitary, pancreatic islet and parathyroid tumours. Mice (Men1+/−) deleted for an MEN1 allele develop these tumours. The MEN1 gene encodes a 610 amino acid protein that has been reported to upregulate caspase 8 expression and promote apoptosis. To characterize the functional effects of menin loss in vivo, we asse...

Background: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex to produce glucocorticoids. 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) or the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 & 2 ...

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease resulting from adrenal unresponsiveness to ACTH. Patients present in early childhood with hyperpigmentation, hypoglycaemic episodes and seizures secondary to glucocorticoid deficiency. If left untreated this condition is fatal. Mineralocorticoid production is normal. Mutations in the ACTH receptor have been well described and account for approximately 25% of cases. We describe 3 additional novel mut...

FGD is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex to stimulate glucocorticoid production. The disease is caused by mutations in ACTHR or MC2R in 25% of cases, termed FGD type 1, and has previously been linked to a locus on chromosome 8q12.2-21.2 in a single family with FGD type 2. We have recently described a novel gene (FGD2) that when defective is a second cause of FGD. Sequencing of this gene in 100 FGD2 patients ha...

Expression of the ACTH receptor (MC2R), a 7 transmembrane GPCR, has been difficult to achieve in cell lines that are not of adrenal origin. Heterologous expression of this gene in many cell lines (CHO, Hela, H295R, HEK293) produces a protein that is trapped in the ER, suggesting that an accessory factor(s) might be necessary to traffic MC2R through the cell. We recently identified such an accessory factor, MRAP that rescues MC2R expression in some, but not all, cell lines. Mut...

Familial Glucocorticoid Deficiency (FGD) [OMIM #202200] is an autosomal recessive disorder resulting from resistance to the action of adrenocorticotropin (ACTH) on the adrenal cortex to stimulate glucocorticoid production. It has previously been linked to mutations in the ACTH receptor (ACTHR) [FGD type 1] and a locus on chromosome 8q, but 70% of cases have no known cause. The aim of this study was to identify additional loci and genes for FGD using a linkage mapping strategy....