Endocrine Abstracts

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by ACTH resistance resulting in isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Approximately 25% of cases result from mutations in the ACTH receptor (MC2R) and 20% result from mutations in the Melanocortin 2 receptor accessory protein (MRAP). MRAP is a small single transmembrane domain protein that is specifically required for trafficking MC2R to the ce...

Pseudoexons resemble true exons by current bioinformatic criteria and may outnumber true exons by 10:1. They are, however, never spliced into mature mRNA. A point mutation in the GHR gene results in abnormal splicing of a pseudoexon, leading to Laron syndrome. The GHR pseudoexon lies between exons six and seven and the point mutation is adjacent to the pseudoexon 5' splice site.Our studies aimed to define the elements that normally prevent splicing of this pseudoexon.A...

Familial glucocorticoid deficiency is an autosomal recessive disorder characterised by resistance to ACTH of the adrenal cortex, leading to isolated glucocorticoid deficiency and life-threatening hypoglycaemia. Half of all cases are caused by mutations in MC2R, MRAP, MCM4 or STAR. Recent work in our group has identified defects in nicotinamide nucleotide transhydrogenase (NNT) to be causal in a further 10% of cases. NNT generates the high con...

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 ...

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...

Growth hormone insensitivity, also known as Laron Syndrome (LS), is caused by mutations within the GH receptor (GHR). A 1.5 year-old boy with consanguineous parents was referred with postnatal linear growth failure (length 64 cms, minus 6 SDS). Facial features were typical of LS. Investigation revealed elevated serum GH (1145 mIU per litre) and low IGF-I (4 nmol per litre). Genomic DNA was isolated from peripheral blood leucocytes and all GHR exons, including intron-exon bound...

Congenital isolated ACTH deficiency (IAD) is a rare inherited disorder that is clinically and genetically heterogeneous. Patients are characterised by low or absent cortisol production secondary to low plasma ACTH despite the absence of structural pituitary defects and normal secretory indices of other pituitary hormones. When tested, there is often no ACTH response to exogenous CRH. Onset may occur in the neonatal period, but often is first observed in later childhood. Candid...

Aim: Clinical acromegaly is characterized by high GH secretion in the presence of high circulating IGF-I levels. We therefore hypothesized that the physiological IGF-I-GH negative feedback loop may be reset in somatotroph adenomas, and we investigated the role of type 1 IGF receptor (IGF-R) and GH receptor (GHR) by quantifying mRNA expression in somatotroph tumours, and investigated the possible presence of mutations of the GHR gene.Methods: Pituitary t...

Background: GH Insensitivity (GHI) is usually caused by mutations in the GH receptor (GHR). Our centre previously described the first GHR pseudoexon mutation (42700896A>G, c. 618+792A>G). Inclusion of this 108bp pseudoexon is predicted to lead to in-frame insertion of 36 amino acid residues in the dimerization domain of the GHR. This results in defective trafficking rather than impaired signalling, causing partial loss-of-function and moderat...

Objective: Variability in growth hormone (GH) responsiveness is evident in adult hypopituitary patients receiving recombinant GH (rhGH). Doses vary up to 4-fold for unexplained reasons. Deletion of exon 3 in the GH receptor (d3-GHR) has been linked to an increased response to GH treatment in children, although data are conflicting. We investigated the role of the d3-GHR polymorphism in determining GH responsiveness in adult GH deficient patients.Methods:...