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Possible Cause For Pots? Mutation On Net Gene


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Dana, I know EXACTLY how you feel..........this is a never ending circus, and I am sicke to death of the research. I think on some days I am sicker of the research than I am of the sickness......does that even make sense......hmmmm

Getting ready to go on this trip in December, for purely medical reasons, and its 6 months away and all I am doing other than being sick is doing the leg work to get to the correct Doctors with the correct records.

Meanwhile the local Docs are running me through a million hoops trying to find their own answers, some not listening to me. Wanting to run their own tests and wanting to try their own treatments at the same time they are signing letters to send me out of the state for more sophisticated help.

It's exhausting.

With my health going the way it is we figured one last shot for answers, so be it this is the big trip to all the specialists and then.... I'm DONE, no more, what I have here with my PCP with whatever we find will have to be good enough.

Huge Hugs, find peace in your singing when you can.

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Have to agree with Dana. I'm tired of researching and going around in circles. But, I do believe with the gene testing that I'm getting some answers and I'm thrilled that I'm finding connections with my problems to genes. Only, like was earlier said, finding the way to turn off the activated genes may be years away. But, with stem cell research and all the other research on genes and those type of things ---it may not be as far off as some people think. It may be a ways off with medicines - but, I'm thinking we can find some solutions with herbals and those we can do right now. Like for example - it was recently figured out that I have distolic dysfunction of my left venticle of my heart. What can I do about it? Believe it or not one of the things I've been telling people about for the last few years ----and I had stopped taking -----olive leaf. I'm recently also gone back on Tumeric and Ginger and it is helping me TONS. Since I have some autoimmune and inflammatory things going on ---these are some of the best things to modify TNF and cytokines. Seems to be making a difference and it helps with inflammation and pain too. Win, win ---here. So, I'm not giving up and since I'm more into alternative things any way ---this will be my focus ----since medicine may be a ways away.

Oh, thanks Dana for telling me which article he was talking about - yeah, read that one and did send it. I have a friend that maybe can get the full article - I'll ask her. I think the study on epigenetics will be a great, exciting study and hopefully they will figure some things out. If a gene can be activated via vaccines, environmental pollutants, viruses etc. there should be a way to deactivate those same genes. It's just figuring out what the right combination is. Our bodies are wonderfully made and with time, possibly some of it may be figured out.

My PCP has gone on to do some testing on me recently and we are figuring out more things too - lots of it in connection to the gene testing I had done. What that showed as a possiblity for me ---is, in fact, what is starting to show up with science. Yayyyyyy!!!!! Now to figure out what to do about it. Hmmmmm!!!!

Dana, I hope this is your needle in the haystack and then you can maybe work on things from that angle.
Issie

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Rich,

Aside from being able to stop researching, it also has implications for my family and if I ever have children. I could pass this on to them.... :( One of my parents had to give me the "A" allele. I'd suspect my dad considering his health problems, but out of his parents I don't know where he got it from, so I'm thinking there has to be more to it than just carrying an A allele. Probably a trigger of some sort to cause even further reduction in NET protein.

In recent months, I've suspected my dad has a mild form of POTS and doesn't know it. I think my brother also probably has it too. He's been showing signs of it for the past 2 years, but it is no where near as severe as mine. However he has heat intolerance and is starting to get exercise intolerance too. He said he is having trouble doing a workout video he used to be able to do without any problems. He is 22 years old and that's around the age when I became disabled. I've been getting texts from him suggesting he is in the beginning stages of what I went through. I'd be completely shocked if my sister or mom had it because even though they have their own health problems (my sister had a cancerous brain tumor at 25), it does not act like POTS.

Rama,

In one study, scientists predict the mutation I have has a 0.43% frequency in the population, so it is rare, but certainly not specific to one family. The other mutation A457P, yes is extremely rare and I probably don't have that one, but won't know unless I have my entire gene sequenced.

I just need to find out if this mutation can cause POTS like symptoms. If it can, then I can start looking for specific medications to help this. Do you know of anything medications that increases NET activity or would in the very least counteract this?

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There is something called transcriptome genome sequencing that would look at this.

Id suggest any POTS patients to spend the $20 on this article - Im reading it now and i feel like popping champagne.

Rama, after reading the article I too feel like it offers a highly plausible mechanism for POTS. What frustrates me is their conclusion, because further research can take 10-30 years.

I'm going to see my rheumatologist to discuss the findings.

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I'm not thinking this article is telling us anything that we haven't already figured out. Of the 20 something that this research was conducted with they speak of another snp that was consistent with all these people with POTS - it doesn't show what their markers are. It also doesn't show what the markers in the ones without POTS were. (Dana, can you chime in on this one - since it's you who discovered this.) Some of us have compared our snp's and we come up with the common markers for this snp and we know we have HyperPOTS. Unless, this would maybe help with subsets - not sure this is helpful. Those of us that are looking into genetics have discovered mutations in the methylation pathways and this can be consistent with epigenetics. It is possible that something turned on the genes and these same genes can be turned off. But, the turn on of these genes could very possibly have happened at or before birth and therefore are just genetic flaws or dysfunctions. In others where there are known illness and then someone got POTS - it may be more plausible that whatever turned on the genes - maybe can be turned off. But, finding the mechanism to turn them off - when we really don't know what turned them on ---may be years in coming. Working on things that regulate cytokines and things that maybe cause inflammation - may be an option. I've said for years - I think - that inflammation may be playing a big role in all our problems.

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There seems to be some sort of dysfunction with NE even in those without high standing levels above 600. There appears to be a sympathetic response regardless - whether or not NE is the culprit or not - time will tell.

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I'm not thinking this article is telling us anything that we haven't already figured out. Of the 20 something that this research was conducted with they speak of another snp that was consistent with all these people with POTS - it doesn't show what their markers are. It also doesn't show what the markers in the ones without POTS were. (Dana, can you chime in on this one - since it's you who discovered this.) Some of us have compared our snp's and we come up with the common markers for this snp and we know we have HyperPOTS. Unless, this would maybe help with subsets - not sure this is helpful. Those of us that are looking into genetics have discovered mutations in the methylation pathways and this can be consistent with epigenetics. It is possible that something turned on the genes and these same genes can be turned off. But, the turn on of these genes could very possibly have happened at or before birth and therefore are just genetic flaws or dysfunctions. In others where there are known illness and then someone got POTS - it may be more plausible that whatever turned on the genes - maybe can be turned off. But, finding the mechanism to turn them off - when we really don't know what turned them on ---may be years in coming. Working on things that regulate cytokines and things that maybe cause inflammation - may be an option. I've said for years - I think - that inflammation may be playing a big role in all our problems.

The important part of the article is essentially providing data that despite having normal SLC6A2 genes, POTS patients still have NET protein deficiencies that can be attributed to external factors (transcription factors, histone factors, etc). So the mechanism of NET protein deficiency is given validity again.

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I'm not thinking this article is telling us anything that we haven't already figured out. Of the 20 something that this research was conducted with they speak of another snp that was consistent with all these people with POTS - it doesn't show what their markers are. It also doesn't show what the markers in the ones without POTS were. (Dana, can you chime in on this one - since it's you who discovered this.) Some of us have compared our snp's and we come up with the common markers for this snp and we know we have HyperPOTS. Unless, this would maybe help with subsets - not sure this is helpful. Those of us that are looking into genetics have discovered mutations in the methylation pathways and this can be consistent with epigenetics. It is possible that something turned on the genes and these same genes can be turned off. But, the turn on of these genes could very possibly have happened at or before birth and therefore are just genetic flaws or dysfunctions. In others where there are known illness and then someone got POTS - it may be more plausible that whatever turned on the genes - maybe can be turned off. But, finding the mechanism to turn them off - when we really don't know what turned them on ---may be years in coming. Working on things that regulate cytokines and things that maybe cause inflammation - may be an option. I've said for years - I think - that inflammation may be playing a big role in all our problems.

1. only one patient EVER has been found to have a polymorphism that effected NET function genetically despite over 300 being screened so I doubt that you have had genetic screening that demonstrated 'hyper POTS'.

2. methylation pathways - your getting cellular methylation mixed up with epigenetics when they are not in any way connected.

3. your comments about turning genes on and off are based on an assumption that people dont understand epigenetic regulation.

4. the cytokines involved are not traditionally pro inflmmatory cytokines, byt some may play a role in inflammation. I doubt many of these can be easily regulated since their function is poorly characterised - and they are numerous.

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There is something called transcriptome genome sequencing that would look at this.

Id suggest any POTS patients to spend the $20 on this article - Im reading it now and i feel like popping champagne.

Rama, after reading the article I too feel like it offers a highly plausible mechanism for POTS. What frustrates me is their conclusion, because further research can take 10-30 years.

I'm going to see my rheumatologist to discuss the findings.

It is very impressive. NET inhibition can explain more than just about any other mechanism bar perhaps the ANG ii crowd. Peripheral vasoconstriction but central reductions in sympathjetic mediated vasoconstriction, tachycardia, etc.

cytokine inhibitors are fairly expensiev and highly regulated so I doubt you'll get them prescribed based on one newly published study :)

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1. only one patient EVER has been found to have a polymorphism that effected NET function genetically despite over 300 being screened so I doubt that you have had genetic screening that demonstrated 'hyper PO
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Genetic screening with 23&me and prometheses has found markers that are indicative of some of the symptoms related to dysautonomia - the type is not identified. And yes, many of the snps related to NET are tested by 23&me and we can compare our snps to others and also look up data to see if our genotype is the more common type or if it is rare. I know Dana has come up with one snp that is considered not as common. I hope that means she has found her answer. Just because they have found one patient that has a different NET marker doesn't mean that in the WHOLE WORLD there isn't another one. Where there is one - there are possibly others. It just may mean that the others with the rare gene hasn't been tested.
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2. methylation pathways - your getting cellular methylation mixed up with epigenetics when they are not in any way connected.

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No, I'm not. There are and can be genetic mutations in the methylation pathways and with these mutations there can be a possible epigenetics relationship. If a gene has mutated and turned on than very possibly it can be turned off.

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3. your comments about turning genes on and off are based on an assumption that people don't understand epigenetic regulation.

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What? I think the idea of being able to tweak a mutation in a gene is about as good of an idea as any of the others out there. With the science with stem cells and them helping with cancer with it - why not have it help us in other ways. If there is a way to turn off an activated mutation in a gene ---why not do it? If they can turn off/or tweak the activated genes that causes cancer - there may be a way to turn off/or tweak whatever is causing dysautonomia too.

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4. the cytokines involved are not traditionally pro inflmmatory cytokines, byt some may play a role in inflammation. I doubt many of these can be easily regulated since their function is poorly characterised - and they are numerous.

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Let us hope that if there is a way to work on cytokines and that would help with our dysautonomia and/or autoimmune disorders - we can find a way to do it. I know with my studies there are herbs that will work on these things. Two of them are ginger and turmeric. I'm finding that they both help pain tremendously. What other benefits they may be having - time will tell. But, it is known that turmeric helps to modify cytokines like TNF and others. I'm hoping it will improve my newly found autoimmune issues.

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The science seems far off to me. This is based on one pair of twins really?

Yes something is obviously going on with our NE transportation system. But that's no surprise right? NE is a major sympathetic neuro transmitter, we have dys function of our sympathetic system right? The key is looking closer not at genes but at function paths and interaction with synapse..

I agree finding out that some gene is altered, in anyway, will help us have more proof we have dysfunction, but gene testing is not cheap and often not covered by insurance. I know I have pots already from my titl test, I know my ne is somewhat high from testing. Now what? Is the it the high part of is it the my sensitivity to it. Am I allergic to my own NE at a certain level, or at a certain level does it trigger some other wackiness? Come on there has to be more here!

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Im out of this thread.

Dana - In relation to the polymorphism of NET - its worth getting checked out but there is one specific ploymorphism that was found to correlate with decreased NET expression so Id try and get tested for that.

Rich - imnpaired NET function has been implicated in POTS for years. Im not really sure what your trying to say there mate.

Issue - see my previous post. Working on cytokines - what exactly does that mean?

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I think you are missing the point of my thread. I have something going on with the gene and you keep saying that the gene is normal. lol

Apparently I did miss the point there for a while by responding to others.

Research groups have looked at multiple polymorphisms of the NET gene and only the one mentioned in the Shannon study was found to be haev functional consequences that caused reduced protein expression. In other words its unlikely but possible that the polymorphism you have mentioned has some sort of etiological link to your POTS.

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Issie, the information I was looking for with the SNP's is actually in the supplemental data for the study found here at this link!

"Association ρ-values of all SNPs with POTS diagnosis are presented in Table IV. Compared with healthy subjects, the rs5564 T genotype was found to be significantly associated with the diagnosis of POTS (ρ=0.0014) following adjustment for multiple testing. The rs5564 polymorphism is located in the splice site consensus sequence of exon 5. Whether the rs5564 genotype has a functional affect on mRNA processing remains to be established." I really question this to be honest. I am AA which would be TT. However, AA is the most common result. HapMap puts the CEU population as having 91.1% frequency for AA.

Rama,

There are currently 16 known missenses in the SLCA2 gene (NET). You can see them listed here at this website. One was found just in 2009 (T283M) and it was shown to cause a POTS like syndrome in a woman. Her standing HR increased by 26 bpm and her standing NE was 595. The decrease in NET with T283M is very similiar to those with V245I. I think this alone suggests you can have POTS with other NET mutations besides the one the twins had.

The epigenetic supplemental data PDF is more interesting to me than the actual study....Those who did in fact carry rare alleles on V245I (the one I have) and V69I (23andme doesn't test this one), were all healthy subjects. The researchers for this study say that V245I in vitro did not alter NET function. But they took a study from 2005 and disregarded a newer one from 2009 where they actually tested people and there was in fact a 30-40% decreased NET function and a significant decrease in DAT function. I checked out both studies and they are from the same researcher I emailed and have yet to hear back from. I dunno what to make of this conflicting information.

It sounds like the epigenetic study was done many years ago because it said they used the latest dbSNP build, 124. Meanwhile, they are on build 137 now. 124 was new back in 2005. I'm kind of hoping the dbSNP build was a typo because a lot has happened in 7 years and their conclusions that the minor alleles found in the healthy subjects were meaningless seems...irresponsible. But if they had to admit they were meaningful, then their entire study would have crumbled.

After more research and time to think about all of this, I believe it takes a combination of things to occur in order to have POTS from low NET function. The one genetic mutation the twins had caused a 98% decrease in function...That's huge. But perhaps other mutations in NET with smaller decreases like 30-60% may not affect everyone unless you also have an epigenetic change too.

I am aware a lot of these SNP's are being tested for ADHD. I definitely don't have ADHD. If anything I have an insane amount of focus, concentration and I can become obsessive with things very easily/quickly. That's the exact opposite of ADHD. I have an usual ability to recall images too. It's like I have a constant radar on looking out for anything out of place or not the way it was when I last saw it or left it. My husband is amazed by it. lol

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Thanks Dana for the info and will you let us know what they say in regard to your e-mail. As I stated in my earlier post - just because they found only one person with a rare allele on a snp doesn't mean that there aren't more or more people with rarities. We know there is some sort of dysfunction with NE and NET. I agree with you that there is probably more to it than just these abnormalities. I find it very interesting what you are discovering and although I'm still a student on this one (it's still way over my head) I find it fascinating.

Since we have also found methylation mutations could it be playing a part in this? Just the mutations alone - make some serious dysfunctions in the body.

I've been friends with Dana for a long time and I can vouch for her focus and attention to detail. She's one of the smartest people I know. Very talented too. :)

Issie

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Aww thanks Issie, That's really nice of you. :)

I'm hoping I ever hear back from them. haha! My doc said he won't talk to me about this until my next appt... I'm not sure what to make of that. Took them a week to call me back. They've pushed back every single appt I've had with him so far, so I'm skeptical this one will even stick. Blah just sort of complaining right now. I just feel like these docs really do not care.

I wait until July 30 to hear what he has to say.

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Rama, i think its just the language barrier mate. I'm not saying they dont know what they are doing or aren't brilliant in fact. I'm saying they need to do a lot more studying before it can be considered conclusive. When I look back at a lot of POTS research or articles brought up on the forum over 5 plus years ago, it hasnt lead to much yet in terms of treatment. You of all people should know this because you have posted on all of your supplement or herbal experiments on here. If there was some treatment looming around the corner where 50% of us could all have benefits from then I would understand. But If you look at the study carefully they say they tested these twins, detected the mutation, but then when they tested other pots patients later on it wasnt conclusive. So it would be great if they were on to something all I'm saying by "far off" is a lot more testing needs to be done first.. And I think in just about every POTS article I've read at the conclusion of the article it always says but more studies need to be done... In the nine or so years you have known that you had pots how may discovers turned out to be nothing...

On Dinet.org's list of POTS causes there are some 26 possible causes listed, this one not included.. So I'm just not excited about it they, we'll see..

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