Endocrine Abstracts

The calcium-sensing receptor (CaSR), a class C G-protein coupled receptor (GPCR) is critical for calcium homeostasis. The presence of CaSR at the plasma membrane (PM) is regulated by a balance between internalisation via clathrin-mediated endocytosis, and agonist-induced PM insertion from intracellular receptor pools, in a mechanism known as agonist-driven insertional signalling. Recently, mutations of the clathrin-mediated endocytic adaptor protein-2 sigma subunit, AP2σ,...

Familial hypocalciuric hypercalcaemia type-3 (FHH3) is caused by loss-of-function mutations of the sigma subunit of adaptor protein-2 (AP2), a ubiquitously expressed heterotetrameric protein with a fundamental role in endocytosis of transmembrane proteins. FHH3-associated AP2σ mutations impair internalisation of calcium-sensing receptor (CaSR) giving rise to FHH. CaSR predominantly signals via Gαq/11 leading to intracellular calcium release, and activation...

Hereditary hypercalcaemia can be a diagnostic challenge. We present a family with autosomal dominant hypercalcaemia that illustrates this. A 48-year-old man was referred with asymptomatic long standing hypercalcaemia (2.8–3.04 mmol/l), with plasma PTH levels between 45 and 48 ng/l (normal 15–65), and a high urinary calcium excretion, (24 h calcium collection 10.4 mmol/l (2.5–7.5), with high calcium excretion indexes) all consistent with primary hyperparathyroidi...

Mutational analysis of the calcium-sensing receptor (CaSR) is frequently undertaken to confirm a diagnosis of familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemic hypercalciuria (ADHH). However, functional characterization of these CaSR mutations to demonstrate loss-of-function for FHH mutations and gain-of-function for ADHH mutations is infrequently performed. We demonstrate the importance of pursuing in vitro studies that investigate the functiona...

Background: Primary hyperparathyroidism (PHPT) is commonly diagnosed after the fifth decade of life. Current guidelines suggest that young patients with apparently sporadic PHPT should be screened as potential index cases for the multiple endocrine neoplasia type 1 (MEN-1) syndrome.Aim: To determine the prevalence of mutations in the MEN1 gene in young patients presenting with apparently sporadic PHPT before the age of 40 years.Met...

Ectopic (or ‘illegitimate’) transcripts, which have been widely used to study disease-causing mutations when samples from the appropriate tissue cannot be obtained, are generally faithful representations of the normal tissue-specific counterparts. Here, we report the occurrence of ectopic transcripts of the hepatocyte nuclear factor-1 beta (HNF-1β) gene, mutations of which may result in maturity onset diabetes of the young type 5 (MODY5), the renal cysts ...

Parafibromin is a tumour suppressor protein, encoded by the gene responsible for the hyperparathyroidism-jaw tumour (HPT-JT) syndrome, which is an autosomal dominant disorder, characterised by parathyroid tumours, ossifyfing fibromas, renal and uterine tumours. Parafibromin is a component of the polymerase-associated factor 1 (PAF1) complex and interacts directly with β-catenin, although these functions do not fully explain its role in tumourigenesis. To further investiga...

MicroRNAs are highly conserved non-coding RNAs that regulate diverse cellular processes. Altered microRNA expression is observed in many human cancers and microRNAs may have tumour suppressor or oncogenic properties. One group of putative tumour suppressor microRNAs is the let-7 family whose expression is reduced in several human tumours, and which inhibit the expression of several oncogenes including HMGA2 and K-Ras. Let-7 expression have also been observed to b...

Background: Mutations in the UMOD gene, which encodes the Tamm-Horsfall Glycoprotein (THP), cause FJHN, an autosomal dominant disorder characterised by gout and renal failure. THP is a 640 amino acid glycosylphosphatidylinositol-anchored protein, containing three Epidermal Growth Factor (EGF)-like domains, a cysteine-rich region and a Zona Pelllucida (ZP) domain. THP is translated into the Endoplasmic Reticulum (ER) lumen, glycosylated in the Golgi apparatus, trafficked...

Delayed puberty may occur in some boys affected with X-linked Spondyloepiphyseal dysplasia tarda (SEDT), which is caused by mutations of the gene encoding a 140 amino acid protein designated Sedlin. Sedlin interacts with the pituitary homeobox 1 (Pitx1) and steroidogenic factor 1 (SF1) transcription factors, which are involved in the development and regulation of the hypothalamic-pituitary-gonadal axis. We have therefore investigated the hypothesis that SEDT associated mutatio...