Endocrine Abstracts

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...

Adaptor protein-2 (AP2) is a heterotetramer of α, β, μ, and σ subunits that is pivotal in clathrin-mediated endocytosis and facilitates internalisation of plasma membrane constituents such as the calcium-sensing receptor (CaSR). AP2 σ subunit (AP2σ) missense mutations (Arg15Cys, Arg15His and Arg15Leu) result in familial hypocalciuric hypercalcaemia type 3 (FHH3) and decrease the sensitivity of CaSR-expressing cells to changes in extracellular calc...

Autosomal dominant hypocalcaemia (ADH) is a disorder that needs to be distinguished from hypoparathyroidism, as ADH patients are at risk of nephrocalcinosis and renal failure when treated with activated vitamin D preparations. ADH types 1 and 2 are due to gain-of-function mutations of the calcium-sensing receptor (CaSR) and G-protein α 11 (Gα11), respectively. CaSR targeted drugs, known as calcilytics, rectify the gain-of-function associated with ADH1-causing mutatio...

The hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by germline mutations of the dual zinc-finger (ZnF) transcription factor, GATA3. To date, 51 GATA3 mutations have been reported, which can be divided broadly into three structural-functional classes: i) mutations that lead to a loss of DNA binding and involve ZnF2; ii) mutations, usually of ZnF1, that bind DNA but result in reduced DNA binding affinity; and iii) mut...

Osteoarthritis (OA) may be associated with endocrine disorders such as hypothyroidism, obesity, primary hyperparathyroidism or acromegaly, although often its cause remains undefined. To facilitate investigations of the underlying molecular mechanisms of OA we have investigated N-ethyl-N-nitrosourea (ENU) mutant mice using a genotype-driven approach in which candidate genes are examined for mutations. One such investigated gene is growth and differentiation factor...

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...

GATA3 mutations cause the congenital autosomal dominant hypoparathyroidism, Deafness and Renal dysplasia (HDR) syndrome. GATA3 belongs to a family of dual zinc-finger transcription factors that recognise the consensus (A/T)GATA(A/G) motif and are involved in vertebrate embryonic development. We investigated a HDR proband for GATA3 abnormalities. Venous blood was obtained after informed consent, as approved by the local ethical committee, and leukocyte DNA extracted. GATA3 spec...

The calcium sensing receptor (CaSR) is a G protein coupled receptor that is expressed in type A intercalated cells of the distal convoluted tubule and cortical collecting ducts, where it is involved in renal proton excretion. We have therefore investigated the Nuf mouse, which has an activating CaSR mutation (Leu723Gln) that leads to hypocalcaemia, hypercalciuria, renal calcification, a urinary concentrating defect, and cataracts, for disturbances in acid-base homeostasis. Mic...

The calcium-sensing receptor (CaSR) is a G protein coupled receptor that is expressed widely, including pancreatic beta cells where it has been shown to modulate insulin secretion in vitro. However, the role of the CaSR in regulating in vivo insulin secretion and glucose homeostasis remains unknown. We have therefore investigated the Nuf mouse, which has an activating CaSR mutation (Leu723Gln), to determine whether abnormal CaSR function in vivo affects gl...

Familial juvenile hyperuricaemic nephropathy (FJHN), an autosomal dominant disorder characterised by raised serum urate, reduced fractional excretion of uric acid (FEUA), a urine concentrating defect, and progressive renal failure, is caused by mutations in the UMOD gene, encoding uromodulin (Tamm–Horsfall glycoprotein). The FJHN-causing UMOD mutations are missense mutations (>90%) or inframe deletions (<10%), and none result in prematurely truncated...