Key gene may be switched off in some cases of PoTS
8th February 2018
This is the first in a series of articles to be written by Clare Pain, a science and medical writer.
Clare will review significant research papers in an easy-read form to help people who are not from a medical or science background to understand them. PoTS UK would like to thank Clare very much for volunteering to do this work.
Key gene may be switched off in some cases of PoTS
PoTS may be caused, in some people at least, when a gene for removing noradrenaline gets switched off, Australian research suggests(1).
Noradrenaline (called norepinephrine in the USA), is a neurotransmitter chemical produced by nerve cells in the sympathetic nervous system: the system that swings into play in times of danger to produce the classic ‘flight or fight’ response we need when faced with a threat.
But that’s not all the sympathetic nervous system does. It also deals with the effects of gravity when we change position.
When a healthy person stands up, sympathetic nerves in the heart release noradrenaline, triggering the heart to beat a little faster. Other sympathetic nerves stimulate veins, so that blood doesn’t pool in their legs and feet.
In people with PoTS, this automatic response to standing seems to be overdone in the heart, producing an exaggerated increase in heart rate.
When noradrenaline is released from the ends of sympathetic nerve cells, it enters a fluid-filled space known as the synaptic cleft. It crosses the cleft, and then binds to specific receptor molecules on an adjoining target cell which lies on the other side of the cleft. This target cell might be a heart muscle cell, for instance.
The locking of the noradrenaline on to the receptor triggers the wanted effects of the sympathetic system in the target cell.
Normally the noradrenaline – both that attached to receptors, and that still floating in the cleft fluid - gets tidied away by a protein called NET (the norepinephrine transporter protein). The NET protein sucks up the noradrenaline molecules and pops them back into the sympathetic nerve cell, to be reused.
But what if the NET protein wasn’t working properly? Noradrenaline would remain bound to the receptor molecules and floating in the cleft, potentially causing an exaggerated response to standing up. In the heart this could cause too great an increase in heart rate on standing. There would also be effects in the brain, where sympathetic nerves normally slightly constrict the blood vessels when we stand up. With excess noradrenaline in the cleft, the brain blood vessels may become too narrow, leading to dizziness or even blackouts. In other words, if the NET protein isn’t vacuuming away the noradrenaline as it should, we might expect the symptoms of PoTS.
Suspicion has been mounting about the NET protein’s role in PoTS since 2000, when identical twins with severe PoTS were found to have a fault in the gene that codes for it (2). The protein made by the mutated gene was only 2% effective.
But that mutation is exceedingly rare. So far it has only been found in that one family. The vast majority of people with POTS probably have perfectly normal NET genes.
However, the NET protein may still be a key to PoTS, because other researchers gave 18 healthy volunteers double the normal dose of a drug (the antidepressant reboxetine) that temporarily stopped their NET protein from working (3). They developed PoTS symptoms.
Silencing the gene
Since then, evidence has been building that some people with PoTS have little or no NET protein (4,5), even though their NET gene is normal (5). The latest Australian research (1), published in 2017, has found a reason why.
In these people, the researchers suggest, the gene that codes for the NET protein has somehow been switched off. If the gene is silenced in this way, the NET protein can’t be made.
And they think they have found the culprit: a tiny molecule of RNA (ribonucleic acid) called let-7i micro RNA that switches off the NET gene by interacting with a particular binding protein well known to be involved in silencing genes (1).
They found far more of the micro RNA in white blood cells taken from 12 patients with POTS than they did in the cells from 12 healthy people.
And waking it up again
Excitingly, the researchers then tested the effects of a drug that can switch some genes back on. They added the drug, called vorinostat (also known as suberanilohydroxamic acid or SAHA), to white blood cells taken from the PoTS patients.
Vorinostat dramatically increased the amount of NET protein in the cells, presumably by switching the NET gene back on.
But although it works well in white blood cells, vorinostat has not been tested in PoTS patients, and Professor Murray Esler, of the Baker IDI Heart and Diabetes Institute in Melbourne, a cardiologist and one of the study authors, has concerns.
Vorinostat has some unpleasant side effects, he said. We need to look at other drugs that may be better tolerated.
There is still much more work to do, he said. First, it is likely that PoTS may be caused in several different ways and not all people with PoTS are expected to have a silenced NET gene.
Second, so far, research has been done on cells that are easy to get from patients – white blood cells and cells from vein walls. Ideally scientists would like to examine what is going on in the narrow synaptic clefts of sympathetic nerve cells in the heart, but this is not easy to do.
It is quite possible that, because of the narrow clefts, the heart may be particularly susceptible to the effects of NET protein deficiency, explaining the large increase in heart rate when a patient with POTS stands up, said Professor Esler.
Incidentally some drugs act on the NET protein and they are best avoided by people with POTS, he added.
They include the tricyclic antidepressants and ephedrine used in medicine, and the street drugs cocaine and amphetamines.
Gene – the body needs to be able to make many proteins. The instructions for how to make a particular protein are contained in a gene. Each gene contains the instructions to make just one protein – for example, the NET protein. The gene is a small section of a long molecule of DNA (deoxyribonucleic acid).
Neurotransmitter – a chemical released from special regions called synapses that are found at the ends of nerve cells. The neurotransmitter is used to send a message from a nerve cell to an adjacent cell (for example another nerve cell, a gland cell, or muscle cell) that lies across the synaptic cleft.
Cell - a small living unit often specialised for some role – for example nerve, bone or muscle cells. Each cell is enclosed in a membrane.
Code – genes hold the instructions for making proteins. The instructions are written in a code which is based on the sequence of parts of the DNA molecule. This is known as ‘the genetic code’ and genes are therefore said to ‘code’ for proteins.
Mutation – sometimes genes contain an abnormal piece of code. These are known as mutations. Mutations may be beneficial, harmful or make no difference to the function of the gene.
1. Abdul Waheed Khan et al. NET silencing by let-7i in postural tachycardia syndrome. JCI Insight, 2017.
2. John R Shannon et al. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. The New England Journal of Medicine, 2000.
3.Christoph Schroeder et al. Selective Norepinephrine Reuptake Inhibition as a Human Model of Orthostatic Intolerance. Circulation, 2002.
4. Elisabeth Lambert et al. Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome. Circ. Arrhythmia Electrophysiol, 2008.
5. Richard Bayles et al. Epigenetic Modification of the Norepinephrine Transporter Gene in Postural Tachycardia Syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology, 2012.
This article is outside the scope of the information standard