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MTRR Question

Discussion in 'Genetic Testing and SNPs' started by JNerissa, Mar 21, 2015.

  1. JNerissa

    JNerissa

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    I recently received my 23andMe results and analyzed them for methylation SNPs. I'm heterozygous (AG) on a few, including MTHFR C677T and MTRR A664A, and homozygous (GG) on MTRR A66G.

    I'm trying to figure out what the MTRR mutations mean, in particular, as far as what is going on in my body.

    I know my MTRR A66G is bad news, but how much, if at all, should I worry about my MTRR A664A? I've looked for more detailed info but have been unable to find it.

    Also, as I understand it (and please forgive my simplified explanation), MTRR is involved in recycling used methylcobalamin back into a useable state. The solution is to take large doses of methylcobalamin to compensate. But with this mutation, doesn't that also mean that my body is accumulating a larger than normal amount of used methylcobalamin? What happens to it, and can it cause any additional problems?
     
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  2. Valentijn

    Valentijn Senior Member

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    @JNerissa - As a rule, MTRR mutations have to be homozygous to have any significant impact, or compound heterozygous. So A664A +/- shouldn't be doing anything, really.

    MTRR A66G indicates that methylcobalamin recycling for MTR is happening at about 30% of the usual rate. But pretty much everyone has some reduction in the functioning of that gene ... looking at 23andMe data for 31 random people shows an average of about 60% of optimal functioning for that gene.

    Excess B12 can be stored in the liver or it is excreted in the urine. And it's not so much that the methylcobalamin gets "used" and transformed somehow, if I understand correctly, but rather that MTR needs to hook up with methylcobalamin to do its job. Technically it's the MTR getting recycled and put back into action by MTRR, and the methylcobalamin is not being recycled (though perhaps it is being reused).
     
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  3. JNerissa

    JNerissa

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    Ahh, OK, that makes sense.

    I'm one of those rare CFS sufferers who was more or less cured by taking methylfolate and methylcobalamin, which, to me, means that I didn't really have CFS, I had a severe vitamin deficiency. I say more or less because it took me 9 years to discover it and I seem to have some lasting neurological damage.

    Yet I guess my genetic profile suggests that my impairment shouldn't be that bad? Are there other SNPs I should pay attention to? I ask because I have two children and I want to know if they have the same risk.
     
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  4. Valentijn

    Valentijn Senior Member

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    There are a few possibilities. One is that there are a lot more MTRR mutations tested by 23andMe which aren't listed on the Genetic Genie report. I have a preliminary list of those on http://forums.phoenixrising.me/index.php?threads/interesting-mtrr-variations.24551/ though I'm also working on integrating them into a report.

    Another issue is that many genes are involved with absorbing and transporting B12. Some other B12 genes are GIF, TCN1, TCN2, ABCD4, CUBN, MUT, MMAA, MMAB, MMACHC, MMADHC, LMBRD1, LMBRD2. There might be others, but I think that's all of them.

    There are also a lot of B12-related mutations which aren't tested by 23andMe at all. They're typically looking at a few SNPs likely to have an impact on every gene, when there are hundreds of other relevant SNPs on each of those genes that are untested.

    And there maybe benefits to B12 supplementation unrelated to deficiency. I take mega doses twice per week - far far more than I should need for methylation. It reduces/removes my ME-related pain and help with my OI a bit. I don't feel healthy as a result of taking it, but I feel a lot worse if I don't. If I recall correctly, hydroxoB12 at least acts as an antioxidant, and can impact vasoconstriction and such - I could be wrong though, it's not something I've really looked into.

    And finally, the functioning of genes can be impacted by external factors. So even if every B12 gene is 100% normal, the expression of those genes might be impacted by other genes, or illness, or environmental factors, etc.

    23andMe data just lets us have a peek at one small corner of the entire picture. There's still quite a lot going on which we can't see.
     
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  5. JNerissa

    JNerissa

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    Thanks!
     
  6. unpc

    unpc

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    This stuff is pretty complicated. There are a few things going on. If I recall correctly slowing this path reduces the recycling of homocysteine to methionine and hence production of SAME. Another part is that cobalamin needs to be reduced from the +3 state to the plus 1 to work. It is that reduction which fails. I think the enzyme is zinc based and that that is also oxidised. I think there may be another reaction which I have forgotten. I don't think that it is a lack of MeCbl per se. I am not sure if new MeCbl is in the +1 form I suspect not..
    I suspect that the reduction failure may be due to oxidative stress which apparently occurs in 20% of cases of chronic illness. Glutathione is the primary antioxidant. The load on this can be reduced by ascorbic acid which is apparently better at some antioxidant tasks. If I recall correctly particularly dealing with super oxide in the mitochondria. As I have 3 homozygous SOD snps I am trying this with initially 1000 mg of ascorbic acid. I would prefer smaller more frequent doses. Unfortunately I can't do an oxidised /total glutathione test as my dr just throws her hands up in horror at technical stuff she doesn't understand.
    Another factor is that the levels of oxidised glutathione seemingly divert the body away from energy production to glutathione production.
    As I say my understanding is incomplete and the research complex, so my hypothesis is tentative. However there is an old report of a case of electron chain 1 defect treatment using 3g of ascorbic acid and either ALA or riboflavin? as alternative electron donors getting a girl out of a wheelchair and walking in a few days. Unfortunately I can't find the reference.
     
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