More Evidence Net Deficiency Is Associated With Pots

[ramakentesh]

What does NET deficiency do?:

http://www.ncbi.nlm.nih.gov/pubmed/18187607

Orthostatic tachycardia, blunted NE responses to standing, weird baroreflex responses...

Do cytokines suppress NET gene expression?:

http://www.ncbi.nlm.nih.gov/pubmed/21241805

Does NET knock out increase levels of DAT and SERT leading to lower levels of cerebral dopamine and serotonin?:

http://www.researchgate.net/publication/51238342_Norepinephrine_transporter_(NET)_knock-out_upregulates_dopamine_and_serotonin_transporters_in_the_mouse_brain

[blueskies]

A little info on glutamate - where found: Connections to vaccines, foods, dairy, protein etc.

http://www.truthinlabeling.org/hiddensources.html

Issie

Thanks Issie,

I have to stay away from glutamates (as well as salicylates -- I can only eat low level -- and amines). According to Royal Prince Alfred hospital (Sydney, Australia) allergies and food intolerances diet 'failsafe diet.' citric acid should be fine, along with dextrose and rice syrup. I can eat dairy and do and strangely have been eating mostly non fatmilk for the past couple of years (weight issues) and my skin reactions ('sunburned' when I've not been in the sun) have been getting worse. I'll start by switching back to full cream milk and see if this makes a difference. I had suspected citric acid was a problem and mosty avoided it.

blue

[issie]

Thanks for the post Rama. I'll have to take a moment and read those. I do think NET is a player. Trying to sort out the main issues are challenging. One of those articles describes me to a tee. The higher bp and surges of tachy with sitting and standing and lower bp with lying down. Of course, I can have the tachy things with lying too. So, not sure if that is a mast cell response - but, would almost bet on it. We have some complex issues and sorting them out, hopefully, will give us more relief.

Blue, yes - I do think that watching our diet and glutamate may make a difference. I've found with my MCAS being careful of known triggers is very beneficial for me. As a mast cell release is so similar to a POTS surge - it's hard to tell the difference sometimes. The diet that I'm doing address so many different things - glutamate being one of them. I'm on a vegan, low fat, whole foods diet. I think this is addressing my autoimmune issues and eliminates a lot of known triggers for allergies and mast cell release. There are so many reasons I could list as to why this is making a difference. But, it would take nearly a book to explain the whys of it all. Just glad my doc has me on this path. I have done lots of research on it and figured out lots of things in regards to the diet and the elimination of certain foods and why it should prove to start my body on a healing path.

Issie

[Birdlady]

In this study from 2009, it showed another mutation on NET T283M was seen to cause higher heart rates upon standing. This study also talks about the mutation I have V245I, which affects both NET and DAT. Looks like it affects DAT to a higher degree.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801604/

"We have previously identified and characterized a NET mutation, A457P, that associates with a familial form of orthostatic intolerance, characterized by an abnormally elevated and sustained heart rate displayed upon standing (Hahn et al., 2003; Shannon et al., 2000). In order to assess the influence of T283M on tachycardia, we collected supine and standing heart rates following five minutes of standing in a subset of our samples in the Vanderbilt group. Group mean heart rates for supine, standing, and change upon standing were 84.3+15.4, 94.4+18.0 and 10.1+16.4 bpm, respectively (Fig. 2). The T283M proband demonstrated an increase in heart rate upon standing of 49 bpm (Fig. 2). This change in heart rate was the highest of all subjects and was greater than two standard deviations from the mean. We also administered autonomic function tests to the mother of the proband. We measured heart rate and plasma norepinephrine levels following 30 minutes of upright posture. In adults, the diagnostic criteria for orthostatic intolerance used at Vanderbilt are a standing heart rate change of greater than 30 bpm and a plasma NE level of greater than 600 pg/ml. The heart rate of the mother increased 26 bpm, whereas her plasma NE levels were elevated to 595 pg/ml, very close to the cutoff for orthostatic intolerance diagnosis."

[ramakentesh]

Cool study Dana. Interesting too.

Its interesting that medications that are basically amphetamine based like Ritalin and Adderal seem to help some POTS patients. People assume only becuase of their vasoconstrictive properties but what if its also by upregulating central dopamine? if NET deficiency or non function was found in both POTS and ADHD then meds that help ADHD by upregulating cerebral dopamine might have utility in POTS?? Who knows...

[issie]

Dana, this article is really interesting. Can we determine with our 23&me data if this would be a problem? I still am not sure how to distinguish what is an okay allele and what is a mutated one. I know some of the rs snp's metioned here are on my testing. Just don't know what is okay and what is not. I've got my SLC6A2 raw data printed. Do you have noted issues with this too? I know you had the one mutation that you were trying to get answers about. But, wondered in light of this report if you determined others?

ADHD runs in my family ---it is on both sides of my family. Along with a good bit of dyslexia and certain types of cognitive dyslexia (comprehension both visual and hearing). Maybe, this is the connection in my family with the dysautonomia and other issues. I sure would like to figure this one out.

Issie

[Birdlady]

T283M is a novel missense found in that study, so an RS number has not been assigned. This study alone is why I think Vanderbilt needs to jump off the A457P wagon and start looking at these other missenses on the NET gene.

Figuring out the "bad" allele can be tricky at times. You won't really know if an allele change is significant unless it is tested in a study. Typically though if you are looking at a disease causing allele it will be the less common one in the population. The Minor allele frequency (MAF) will be a low number.

On this page it tells you which allele causes the change in protein. It's only easy if it's a missense though. This is the T283R missense from that study, but it is not tested on 23andme.

http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=rs45564432

This website shows all of the missenses on the NET gene. When I was doing research this site was amazing. If you click on the variant link next to each, it will show you the RS number at the top (if there is one assigned).

http://snpeffect.switchlab.org/sequences?Disease_op=contains&DisFilter=&MutationType_1=&UniProtID=&GeneName=SLC6A2&dbSNP=&items_per_page=30&group_DIF_TANGO=All&group_DIF_WALTZ=All&group_DIF_LIMBO=All&group_Dif_Stability=All

Here's a link to all of the RSID assigned SNP's on the NET gene.

http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?showRare=on&chooseRs=all&go=Go&locusId=6530

Things in green are synonymous. Yellow are introns. Red are in important parts of the gene.

It's hard to explain how to figure out the risk allele in most cases. You kind of just have to play around with it, learn what the different words mean. Wild type, Synonymous, Non-synonymous, missense, frameshift, polymorphism vs mutation etc It will help to get a feel for it.

Just because there is an allele change doesn't mean it changes the function of that protein or that it is a bad thing. Some allele changes causes people to have blue eyes instead of brown etc. Others make you have a different blood type and there isn't a good or bad blood type, so it's good to keep things in mind like that.

I was hoping someone else would take the baton in this area once I disappeared from researching

[issie]

Thanks Dana, I wish I had your brains on this - because if I could understand it like you --I would have for sure taken up where you left off. But, it's still not coming easy for me.

I will read over what you just gave me and hope it clicks. What if you have one part of the allele that is a known cause of an issue ---for example they know that a TT is a problem and you have a CT. Would that mean that you would lean or have a 50% chance of that being an issue? On two of those genes - mine is that way on the ones known to be an issue. (I've been googling all afternoon these two genes to try to figure this out.) Since my sis's kids have ADHD and my dad has depression and there is known dysautonomia in my family that goes back at least to my grandmother. It seems there has to be some sort of genetic connection with it all. (Other than EDS.) But, me figuring it out ---not sure if it will click with me to be able to do that.

Thanks for the info! You amaze me with all this.

Issie

[Birdlady]

It depends on a lot of different factors like where it is on the gene, has it been studied much and there's honestly a lot we just don't know. Typically most damaging mutations are autosomal recessive. That means you need two "bad" copies in order for it to be a problem. There are exceptions to this and those are called autosomal dominant mutations. An example of that would be the A457P NET mutation. The single bad copy actually destroys the good copy of protein in those people.

This PDF might help to just give an overview of things. It talks about this type of stuff.

http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/Changes-that-make-a-gene-faulty-FS5

Typically heterozygous results (that's having 1 "good" and 1 "bad" allele), doesn't affect the gene in such a way that you would have problems. Since you have one working copy, it's usually fine especially in SNPs with a very high occurrence in the population. Many heterozygous results are synonymous. Anything over 20% in the population and I don't even think it's worth discussing unless we find more data to prove otherwise.

This is where more research needs to be done on specific SNPs and genes. You may find a rare SNP in your data and it may mean nothing at all. My dad and I have about 120 discordant SNP's in our data. Those are the types of things that can be interesting to look it. It can suggest there are microdeletions in your DNA. Even these are common and probably don't cause problems. haha Our DNA is very resilient in a lot of ways and yet at the same time very fragile too. It makes me wonder about that family with the A457P mutation. How did that one start? Probably a 1 in a million de novo mutation which has now been passed down the family. It would make me think twice about having kids.

[issie]

I hear you on the kids and passing along genes that we may not want them to get. It's obvious with my sis's kids that they inherited some genes that we wish they didn't have. LOL! I see that in myself and what I got from my parents. But, I guess if we all thought like that the human race would end. Cause, we can't pass on a perfect body if ours is imperfect.

I think, my conclusion is this would take a life time to figure out and I don't think I'll be able to figure it out. Even with the methylation stuff - they are changing the way they are addressing it. I just listened to a seminar tonight on it and what had been done in the past - they are changing the steps that it is done in and using different supplements. I guess with anything new ---there will have to be tweaks and refinement along the way. But, even that seems confusing. Not that I won't keep trying to learn about it. But, I think we have to take what we find helps us and not focus so much on it. We could spend our life trying to learn and sort this all out and in that time - we might could be "living" life - rather then trying to figure it out. LOL! I've taken away some interesting things from this segment of my learning. But, it just seems very complex, complicated and hard to implement. A few of the things I've learned have helped. But other things were a disaster of an experiment.

Thanks Dana for the help and direction!

Issie

[Hummingbird]

Fascinating topic! I just got my 23andme results back about a week ago and was doing a Google search about POTS/NET when I came across your posts. I tested for very high standing norepinephrine, so was interested in this. Would be interested in finding out more!

[Birdlady]

Lauren this thread might be helpful to you.

I listed the RS ID's you can check for most of the missenses. This isn't all of them though because I accidentally missed a few back then.

http://forums.dinet.org/index.php?/topic/20829-possible-cause-for-pots-mutation-on-net-gene/

[ramakentesh]

Not all patients with NET deficiency have elevated norepinephrine according to several studies. Many had normal or perhaps even blunted release.