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23rd Joint Meeting of the British Endocrine Societies with the European Federation of Endocrine Societies

Oral Communications

Development and growth

ea0007oc9 | Development and growth | BES2004

The expression of monocarboxylate transporter 8, as a specific thyroid hormone transporter in human fetal brain and placenta: the effects of intrauterine growth restriction (IUGR)

Chan S , McCabe C , Boelaert K , Visser T , Friesema E , Franklyn J , Kilby M

Intrauterine growth restriction (IUGR) is a significant cause of perinatal morbidity, in particular neurodevelopmental delay, and is associated with fetal hypothyroxinemia. Thyroid hormone is essential for the optimal development of the central nervous system (CNS) in the fetus. Transport of the active ligand triiodothyronine (T3) across the cell membrane is required for its biological effects, initiated by binding of T3 to nuclear thyroid receptors (TR). Recently, the membran...

ea0007oc10 | Development and growth | BES2004

Key mitotic regulators securin and separase in the human fetal brain

Boelaert K , Pemberton H , Kim D , Tannahill L , Chan S , Khanim F , Gittoes N , Franklyn J , Kilby M , McCabe C

Human securin, also known as pituitary tumor transforming gene, plays a critical role during cell division. Ubiquitination of securin during the metaphase to anaphase transition releases its binding partner separase, which cleaves the cohesins holding sister chromatids together. We recently demonstrated reduced securin expression in human fetal versus adult brain, and dissected its role in affecting the proliferation of human embryonal CNS precursor NTERA-2 (NT-2) cells. We ha...

ea0007oc11 | Development and growth | BES2004

KAL-1 and KAL-2 ontogeny and in vitro function in human GnRH-1 developing system

Gonzalez-Martinez D , Hu Y , Schofield J , Kim S , Bouloux P

GnRH is essential on reproductive physiology and behaviour. Early in development, GnRH-1 neurons undergo a migratory process from the olfactory placode (OP) to the hypothalamus. Failure of GnRH-1 migration and abnormal olfactory bulb (OB) characterize Kallmann's syndrome (KS) resulting in hypogonadotrophic hypogonadism and anosmia. The X-linked form of KS is due to a dysfunctional KAL-1 gene, which encodes anosmin-1. An autosomal dominant form of KS results from disrupted K...

ea0007oc12 | Development and growth | BES2004

Alterations of the somatotrophic axis in the obese agouti (Ay/a) mouse

Martin N , Houston P , Patterson M , Carmignac D , Ghatei M , Bloom S , Small C

In addition to obesity, models of abnormal hypothalamic melanocortin signalling display increased linear growth, although the mechanism remains unclear. We have studied the somatotrophic axis in the obese agouti (Ay/a) mouse (male, 12-14 weeks), as a model of an altered melanocortin system. Somatotrophic hormones were measured by radioimmunoassay and hypothalamic neuropeptide expression studied by in situhybridisation.Obese A<...

ea0007oc13 | Development and growth | BES2004

A novel GH variant (Ile179Met) exhibits a decreased ability to activate the ERK pathway

Lewis M , Horan M , Millar D , Easter T , Fryklund L , Gregory J , Valle C , Canete R , Ulied A , Procter A , Cooper D , Scanlon M

The pituitary-expressed growth hormone 1 gene was screened for mutation in a group of 74 Spanish children with familial short stature resulting in the identification of a novel Ile179Met missense mutation. Variant and wild-type GH were expressed in insect cells and functional studies were performed. The Ile179Met variant was shown to exhibit a similar degree of resistance to proteolysis as wild-type GH, indicating that the introduction of Met does not cause significant ...

ea0007oc14 | Development and growth | BES2004

The susceptibility of growth hormone missense variants to proteolytic degradation

Easter T , Millar D , Horan M , Newsway V , Fryklund L , Procter A , Cooper D , Scanlon M , Lewis M

Our previous studies of the gene responsible for the expression of pituitary GH (GH1 gene) have identified 13 novel missense mutations in 52 children with short stature and 154 controls, which occurred more frequently in patients than controls. These mutations result in expression of variant forms of GH with a single amino acid alteration that could lead to conformational changes within the protein, possibly resulting in cleavage sites hidden in wild-type GH becoming ex...

ea0007oc15 | Development and growth | BES2004

Internalization of the GH antagonist pegvisomant

Maamra M , Kopchick J , Strasburger C , Ross R

Pegvisomant is a specific GH antagonist developed for the treatment of acromegaly. Pegvisomant is a GH antagonist molecule with an amino acid substitution that blocks the conformational change necessary for signal transduction and polyethylene glycol (PEG) moieties to improve clinical efficacy. Pegvisomant has a long plasma half-life and its mode of clearance has not been established. We hypothesised that GHR mediated internalisation of Pegvisomant might be one mechanism for i...

ea0007oc16 | Development and growth | BES2004

Responsiveness to growth hormone (GH) is increased in obesity

Gleeson H , Lissett C , Shalet S

Decreased GH secretion and increased GH clearance contribute to low GH levels found in obesity; in spite of which IGF-1 levels are reported as normal. To explain the discordancy between GH and IGF-1 status in obese subjects, an increase in peripheral (hepatic) sensitivity to GH activity has been hypothesized. Previously peripheral responsiveness to GH in obesity has been investigated and reported to be increased, however the use of weight-based GH doses made interpretation dif...