Endocrine Abstracts

Dent's disease is an X-linked renal tubular disorder characterised by low molecular weight proteinuria, hypercalciuria, and nephrolithiasis. The disease is caused by inactivating mutations of a renal-specific chloride channel, hCLC-5, that belongs to the family of mammalian voltage-gated chloride channels (CLCs). Heterologous expression of wild-type CLC-5 in Xenopus oocytes results in chloride (Cl-) conductance, which is markedly reduced or abolished by the m...

The calcium sensing receptor (CaSR) is a G protein coupled receptor that is expressed in the parathyroids and kidneys, where it plays a pivotal role in the regulation of extracellular calcium homeostasis. Patients with activating CaSR mutations have autosomal dominant hypocalcaemia with hypercalciuria (ADHH), which is associated with polydipsia, polyuria, nephrocalcinosis and renal impairment. The Nuf mouse, which has an activating CaSR mutation (Leu723Gln) has been reported t...

Gout, which is commonly associated with hyperuricaemia, affects 0.2% of the population. Hyperuricaemia has a heterogeneous aetiology that may be due to either over production and/or reduced renal clearance, of urate. In order to identify the mechanisms underlying reduced excretion of urate, we undertook positional cloning studies of familial juvenile hyperuricaemic nephropathy (FJHN), which is an autosomal dominant disorder characterised by hyperuricaemia, a low fractional ren...

Investigations of bone disorders which are often inherited have yielded important insights in the molecular mechanisms of bone development, osteoporosis and osteoarthritis. However, these studies have been hampered by the lack of available patients and affected families. To overcome this limitation, we have investigated mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for hereditary bone disorders. Mice were kept in accordance with national welf...

Primary hyperparathyroidism (HPT) is most frequently encountered as a non-familial disorder, but 10% of patients with primary HPT will have a hereditary form, which may occur as an isolated endocrinopathy or as part of a complex tumour syndrome such as multiple endocrine neoplasia type 1 (MEN 1) or type 2 (MEN 2), or the hereditary hyperparathyroidism-jaw tumour syndrome (HPT-JT). Familial isolated hyperparathyroidism (FIHP) is an autosomal dominant disorder characterised by u...

Molecular genetics have yielded many advances in our understanding of endocrine processes. This is particularly true for the mechanisms regulating calcium homeostasis, and the relevance of this to the disorders associated with abnormalities of the extracellular calcium-sensing receptor (CaSR) will be reviewed. The human CaSR is a 1078 amino acid cell surface protein, which is predominantly expressed in the parathyroids and kidney, and is a member of the family of G protein-cou...

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreatic islets and anterior pituitary, which may occur in 95%, >40% and >30% of patients, respectively. Parathyroid tumours, leading to hypercalcaemia, are the first manifestation of MEN1 in >85% of patients, and amongst the pituitary and pancreatic tumours, somatotrophinomas and gastrinomas are more common in patients above the age of 40 years...

The four parathyroid glands (2 superior and 2 inferior) develop from the third and fourth branchial pouches. The 2 inferior parathyroids develop from the third branchial pouch, which also gives rise to the thymus, whilst the 2 superior parathyroids develop from the fourth branchial pouch. Recent molecular genetic studies have identified some of the genes (eg. GATA3, Gcm2 and Hoxa3) involved in these developmental pathways of the branchial pouches and parathyroids, and these wi...

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 ...