Searchable abstracts of presentations at key conferences in endocrinology

ea0003oc3 | Genetics: New Insights into Endocrine Disease | BES2002

A molecular deletional-insertion involving chromosomes Xq27 and 2p25 causes X-linked recessive hypoparathyroidism

Bowl M , Nesbit M , Harding B , Levy E , Schlessinger D , Whyte M , Thakker R

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...

ea0038p186 | Obesity, diabetes, metabolism and cardiovascular | SFEBES2015

Studies of Nuf mice with an activating calcium-sensing receptor (CaSR) mutation demonstrate the CaSR to regulate pancreatic beta-cell mass and glucose homeostasis

Babinsky Valerie N , Hannan Fadil M , Nesbit M Andrew , Hough Alison , Stewart Michelle , Joynson Elizabeth , Hough Tertius A , Bentley Liz , Aggarwal Abhishek , Kallay Eniko , Wells Sara , Cox Roger D , Richards Duncan , Thakker Rajesh V

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...

ea0005p163 | Growth and Development | BES2003

Identification of GATA3 zinc finger 1 residues that are important for interactions with friend of GATA 2 (FOG2)

Ali A , Nesbit M , Thakker R

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...

ea0019p199 | Growth and development | SFEBES2009

Characterisation of the nuclear localisation signal (NLS) site of GATA3

Grigorieva I , Nesbit M , Thakker R

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 ...

ea0005p162 | Growth and Development | BES2003

GATA3 missense mutation disrupts interaction with Friend of GATA 2 (FOG2) and causes the hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome

Nesbit M , Bowl M , Ali A , Thakker R

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 ...

ea0028oc2.8 | Reproduction and bone | SFEBES2012

A calcium-sensing receptor (CaSR) variant, Glu250Lys, present in familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemic hypercalciuria (ADHH) probands represents a functionally neutral polymorphism: lessons for CaSR mutational analysis

Hannan Fadil , Nesbit M Andrew , Cranston Treena , Thakker Rajesh

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...

ea0013oc18 | Novartis Clinical Endocrinology Award | SFEBES2007

Sedlin mutations disrupt interactions with pituitary homeobox 1 (Pitx1) and steroidogenic factor 1 (SF1): potential cause of delayed puberty in boys with Spondyloepiphyseal dysplasia tarda (SEDT)

Jeyabalan Jeshmi , Andrew Nesbit M , Ingraham Holly A , Thakker Rajesh V

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...

ea0003p157 | Genetics | BES2002

Compound heterozygous AIRE-1 mutations in autoimmune polyendocrinopathy type 1

Bowl M , Turner J , Nesbit M , Harding B , Thakker R

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...

ea0034oc4.1 | Thyroid and bone | SFEBES2014

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 exert dominant-negative effects

Howles Sarah , Nesbit M Andrew , Hannan Fadil , Rogers Angela , Piret Sian , Rust Nigel , Thakker Rajesh

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...