Parathyroid Disorders and Diseases Flashcards
What defects or problems could lead to hyperparathyroidism?
Defect in the PTHR, CaSR or parathyroid tumour
What are the symptoms?
Nephrogenic diabetes insipidus Psuedogout Kidney Stone Bone pain Anxiety
How can primary hyperparathyroidism arise?
Non familial sporadic endocrinopathy or as an inherited tumour syndrome
What are the categories of disease?
Single benign adenoma
Multiple hypercellular glands
Parathyroid carcinomas
How is it treated?
Surgically or with radiotherapy
Why might vitamin D/calcium supplementation be needed after treatment?
The unaffected PT would be hypoactive as it was reliant on the affected PT.
What are the different types of inheritance?
Autosomal dominant/recessive
X linked dominant/recessive
What is the effect of mutations on MEN 1?
MEN 1 encodes for MENIN which is a tumour supressor. It regulates oncogene expression as well as interacting with proteins involved in cell cycle control and genome stability.
What is Knudson’s two hit hypothesis?
One hit/mutation occurs in the germ line
Another occurs on the autosome. This is consistant with Men 1 tumours as they seem to harbour both germline and somatic mutations to the MEN1 gene.
What is secondary hyperparathyroidism?
Kidney failure leads to reduced conversion to active D3 and increased phosphate excretion.
How does this differ to primary hyperparathyroidism?
There is hypocalcaemia.
What is the difference between secondary and tertiary hyperparathyroidism?
Tertiary is when secondary has gone untreated and PTH secretion is autonomous/unresponsive to medication.
What are the symptoms of hypoparathyroidism?
Paresthesia
Tetany
Seizures
What are the causes of hypoparathyroidism?
Trauma to parathyroids
Part of a syndrome
Isolated endocrinopathy as a result of genetic mutations.
Where is Glial Cells Missing B expressed in mammals?
Parathyroid glands only.
What happens when it is under/overexpressed in mice?
They lack PT glands/parathyroid adenomas
How were GCMB mutations confirmed in cases of autosomal recessive hypoparathyroidism that were negative for CaSR or PTH mutations?
Restriction enzyme digests were used.
What methods were used to characterise the 4 types of GCMB mutations?
Subcellular localisation
Electrophoretic mobility shift assay (EMSA)
Luciferase reporter assay.
How does a subcellular localisation test work?
Compare the localisation of molecules of interest with that of the wild type as well as a known control molecule that is distributed in the cell. Loss of nuclear translocation signal from a molecule will have a similar distribution within the cell as the control molecule.
How would an EMSA work?
Labelling of target DNA with a probe allows it to be visualised on a gel. If appropriate binding proteins can bind to it then it will retard the passage of the labelled DNA through the gel compared to unbound control DNA. Mutations that prevent DNA binding would result in the labelled DNA travelling the same distance in the gel as the unbound control.
How is a luciferase reporter assay performed?
Insert the expression site/gene of interest into a luciferase vector. Insert the transcription factor of interest into a vector and co-transfect cells with these vectors. The amount of luciferase expressed would reflect the activity of the TF of interest. Controls needed would be blank luciferase/TF vectors as well as the wild type TF.
What is GATA 3?
A transcription factor involved in embyronic development. Mutations cause Hypoparathyroidism, Deafness and Renal dysplasia (HDR) syndrome
What are the symtomps of GATA 3 k/o mice?
GATA3 null mice is lethal
Heterozygotes have hearing abnormalities but no renal problem.
When does GATA3 k/o effect become apparant?
On a low calcium/vit D diet, but not on normal diet. In this case plasma calcium and plasma PTH are reduced c.f. WT. and this is a result of reduced PTH mass
