Endocrine Abstracts

The pathogenesis of pituitary adenomas is poorly understood. One of the first genetic abnormalities identified in association with pituitary adenomas occurs in patients with multiple endocrine neoplasia type-1 (MEN-1), due to mutations in the MEN1 gene, encoding menin. A tumor suppressor, menin associates with histone methyltransferase complexes to change the expression of cyclin-dependent kinase (CDK) inhibitor genes, which may serve as an underlying epigenetic mecha...

Familial glucocorticoid deficiency (FGD;OMIM 202200) results from the inability of the adrenal cortex to produce cortisol in response to ACTH stimulation. Half of all cases are caused by mutations in MC2R, MRAP or STAR. SNP array genotyping of FGD patients of unknown aetiology mapped a disease locus to chromosome 5p13-q12. Targeted exome sequencing of 5p13-q12 in one patient identified a homozygous mutation, p.Ala533Val, in nicotinamide nucleotide transhyd...

Introduction: A unique variant of familial glucocorticoid deficiency (FGD) exists in the Irish travelling community, a genetically isolated population with high levels of consanguinity. Affected children develop hypocortisolaemia and raised ACTH but retain normal renin and aldosterone levels. Children also have short stature, evidence of increased chromosomal breakage and natural killer cell deficiency.Methods: We sought areas of homozygosity common to a...

Background: GH deficiency is associated with reduction in IQ and neural volumes (globus pallidum and thalamus). Significant relationships between IGF1, IGFBP3 and brain volumes have also been described in children born extremely preterm (total brain volume and cerebellum). No published studies report the relationship between markers of GH status and brain volumes in healthy children.Methods: Cognitive assessment, MRI brain and measurement of IGF1 and IGF...

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:...

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease due in ∼25% of cases to defects in the ACTH receptor (melcanocortin 2 receptor -MC2R). Slow progress in characterization of these mutations has been made in view of the difficulty in establishing a functional heterologous cell transfection system for the MC2R, and the best available models relate to the mouse Y6/OS3 cell lines. However we have shown previously that the melanocortin 2 receptor ...

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...

Studies on the lipid emulsion for total parenteral nutrition (TPN) for the premature human infant are limited. We investigated the effects of modifying the fatty acid composition of TPN on the growth and development of the preterm piglet.Piglets delivered by Caesarean section on day 112 of gestation (term = 115 days) received an enteral diet (E: n=6) or TPN solution plus Intralipid (54% 18:2, 25% 18:1; I: n=6) or ClinOleic (17% 18:2, 65% 18:1; C: n=6) fo...

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....

Objective. The aims of our study were to utilise a combination of high fidelity phenotyping, microarray gene expression profiling and conserved synteny mapping between rodent and human genomes to identify genetic determinants underlying human hypertension.Methods. We used the stroke-prone spontaneously hypertensive rat (SHRSP) and a congenic strain (SP.WKYGla2c*) produced by introgressing a quantitative trait locus responsible for blood pressure regulation on rat chromosom...