Endocrine Abstracts

Introduction: Kisspeptin is the endogenous ligand for the G-protein coupled receptor-54 (GPR54 or KiSS1R). During human pregnancy, maternal levels of placental kisspeptin dramatically increase 7000-fold. The physiological significance of this is unknown. A potential target could be the fetal adrenal cortex (FAC), which undergoes rapid growth from 10 weeks gestation, predominantly of the inner fetal zone (FZ). The FZ expresses the steroidogenic enzymes needed for conversion of ...

The hypothalamo-pituitary–thyroid (HPT) axis maintains controlled systemic levels of thyroid hormone (TH). This is achieved through negative feedback via the hypothalamic arcuate and paraventricular nuclei. The effects of thyroid hormone in other hypothalamic nuclei are yet to be elucidated. Administration of triiodothyronine (T3, thyroid hormone) into the hypothalamic ventromedial nucleus (VMN) increases food intake in rats. Thyroid hormone activation and inac...

Background: Thyroid hormone (TH) action is mediated by TH receptors (TRs) α&β. Both regulate gene expression by binding TREs on the DNA (canonical signaling) or activate cellular signaling pathways (noncanonical signaling). Bone is a major TH target and noncanonical TR α & β effects on bone metabolism were suggested. We studied mouse model bones to distinguish between signaling types.Methods: Growth of WT mice and mice with ei...

G-protein subunit α-11 (Gα11), which is encoded by GNA11, plays a major role in calcium homeostasis by regulating parathyroid hormone (PTH) secretion, and germline loss-of-function mutations cause familial hypocalciuric hypercalcaemia type 2 (FHH2). Since Gα11 is ubiquitously expressed, we investigated whether FHH2 is associated with additional non-calcitropic phenotypes by analysing mice harbouring a homozygous germline deletion o...

Hypomorphic CYP24A1 protein coding mutations causing inappropriate 1,25(OH)2D concentrations are associated with idiopathic infantile hypercalcemia and adult-onset hypercalciuria and nephrolithiasis. It is unclear why some cases present with CYP24A1-mediated abnormal calcium handling lack protein-coding CYP24A1 mutations. Non-coding region mutations, e.g. the 3’ UTR, impacting messenger RNA (mRNA) structure have rarely been studied in...

A new genetic disorder has recently been identified that results from mutation of THRA, encoding thyroid hormone receptor α1 (TRα1). Affected children have a high serum T3:T4 ratio, constipation and a variable intellectual deficit, but exhibit a consistently severe skeletal dysplasia. Similar to these patients, Thra1PV/+ mice harbour a mutation that disrupts the C-terminal α-helix of TRα1 and express a domi...

Introduction: As there are scarce data on the clinical case load and multidisciplinary input provided for patients with osteogenesis imperfecta (OI), we performed a survey of patients with OI attending bone and genetic clinics in Glasgow.Methods: Clinical details of 53 children(M:28) and 23 adults(M:9) were obtained by a review of case records.Results: The median age at presentation in children was 4.5 yrs (range 0.2–13.5), wi...

The Wellcome Trust Sanger Institute Gene Targeting Programme is deleting all mouse genes and has already generated 400 knockout mice in a C57/BL6N background with a further 4000 genes targeted in ES cells. Two hundred and fifty new knockouts will undergo limited phenotyping each year. However, the programme lacks a sensitive and sufficiently detailed screen for individual physiological systems, each of which requires high throughput methodology and unique expertise. Thus, we p...

The prohormone T4 represents the majority of circulating thyroid hormones, whereas 80% of the active hormone T3 is derived from T4 by the actions of the type 1 and type 2 deiodinase enzymes (D1 and D2). Local generation of T3 by D2 regulates ligand supply to the nuclear T3-receptor in pituitary, brown adipose tissue and brain, and this enzyme is also expressed in bone. Hypothyroidism in children causes delayed bone age and growth retardation, whereas thyrotoxicosis in adults c...

Hypothyroidism causes delayed ossification and growth retardation. T3 stimulates hypertrophic chondrocyte differentiation whereas unliganded T3 receptors (TRs) repress gene expression and maintain cell proliferation in the absence of hormone. During development the type 3 deiodinase enzyme (D3) inactivates thyroid hormones and prevents T3-access to the fetus. At birth diminishing D3 activity and increasing T3 availability triggers the onset of cell differentiation and correlat...