Endocrine Abstracts

X-linked recessive hypoparathyroidism (XLHPT), due to congenital parathyroid agenesis, has been reported in two related kindreds from Missouri, USA. Affected individuals, who are males, suffer from epilepsy due to hypocalcaemia during infancy, whilst the females are normocalcaemic. Studies have mapped XLHPT to chromosome Xq27 and defined a 1.5 Mbp interval flanked centromerically by Factor IX and telomerically by DXS984. DNA sequence analysis of 4 candidate genes (proto-dbl, A...

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The modulation of pancreatic islet mass represents a novel therapeutic approach for the management of diabetes mellitus. G-protein coupled receptors (GPCRs) regulate beta-cell expansion and proliferation, and the objective of this study was to assess whether the calcium-sensing receptor (CaSR), which is an abundantly expressed beta-cell GPCR, may influence islet mass and systemic glucose homeostasis, and thus represent an exploitable drug target in some forms of diabetes. We c...

GATA3 is a member of the family of zinc finger transcription factors that recognise (A/T)GATA(A/G) motifs in DNA, and mutations that lead to haploinsufficiency cause the hypoparathyroidism, deafness and renal dysplasia syndrome (HDR). GATA3 has two zinc fingers, of which the carboxy-terminal finger (ZnF2) is essential for DNA binding, whereas the amino-terminal finger (ZnF1) stabilizes this binding and physically binds with other multi-type zinc finger proteins, which are refe...

GATA3 mutations cause the congenital autosomal dominant hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome. GATA3 belongs to a family of dual zinc-finger nuclear transcription factors that recognise the consensus (A/T)GATA(A/G) motif and are involved in vertebrate embryonic development. To date, the mechanisms by which GATA3 mutations lead to haploinsufficiency of the GATA3 protein, which comprises 444 amino acids, have been shown to include loss of ...

The hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is an autosomal dominant disorder that is due to mutations of the dual zinc-finger transcription factor, GATA3. The C-terminal zinc finger (ZF2) is crucial for DNA binding, whilst the N-terminal finger (ZF1) stabilizes the DNA binding by ZF2 and interacts with other multi-type zinc finger proteins, referred to as Friends of GATA (FOG), which modulate GATA3 function. The majority of GATA3 mutations causing HDR ...

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...

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...

Autoimmune polyendocrinopathy type 1 (APS1) is an autosomal recessive disorder characterised by hypoparathyroidism, adrenocortical failure, and mucocutaneous candidiasis. The gene causing APS1 is the autoimmune regulator (AIRE-1) gene, which maps to 21q22.3 and consists of 14 exons. The AIRE-1 protein, comprising of 545 amino acids, contains two PHD zinc-finger motifs, a proline rich region and four LXXLL motifs, consistent with its role as a transcription factor. Over 25 diff...

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...