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SNPs for GTP Cyclohydrolase I (GCH1), rate-limiting enzyme for BH4 - relation to NOS

Discussion in 'Genetic Testing and SNPs' started by nandixon, Sep 26, 2012.

  1. jepps

    jepps

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    Many thanks nandison.

    rs10483639 GG, rs3783641 TT, rs8007267 CC are my results, this means, I can build up BH4. But I have MTHFR A1298C, COMT H62H+V158M, VDT Taq, and CBS C699T, all of this heterozygot, and I have histamins, aluminium and bacterials to detoxify, so my BH4 will be depleted, an I will take BH4 2,5 mg/day.

    I wonder, if there is any link, where I can find the risk alleles by myself?
  2. Valentijn

    Valentijn Activity Level: 3

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    Here's a spreadsheet showing rare genotypes for 11 ME/CFS patients and 11 controls. Purple = less than 1% prevalence in the general population, red = 1 - 2.5%, and yellow = 5 - 10% (if there was orange, it would indicate 2.5 - 5%). SNPs where all patients and controls have the same genotype, or no genotype is uncommon (less than 10%) have been excluded, as well as duplicate SNPs where everyone always has the same genotype across those SNPs.

    GCH1.gif

    So basically we have identical results compared to the controls, aside from one outlier, P6 (me). Though the other rare results (and even non-rare results) could of course be having an impact. I've also seen results from another patient here, who was heterozygous for a rare missense mutation on GCH1 at rs41298432 (rare allele A).

    On a personal note, I also have a homozygous MTRR issue resulting in the efficacy of that gene being reduced by a factor of 3.5. How would a potentially slow GCH1 interact with that definitely slow MTRR?
  3. nandixon

    nandixon Senior Member

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    Which SNP(s) in MTRR are you referring to?

    Off hand, I can't think of a perfectly direct interaction between reduced amounts of BH4 and reduced MTRR function. Indirectly, lower amounts of BH4 could promote nitric oxide synthase (NOS) decoupling, which reduces antioxidant status, and thus may make it more likely for cobalamin to become oxidized while MTR is using it for methylation of homocysteine. In other words, it may place a greater burden on MTRR's ability to recycle oxidized cobalamin for use by MTR. Just a guess, though. There may be more direct effects.
  4. Valentijn

    Valentijn Activity Level: 3

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    MTRR A66G. Thanks for the extra info - someone mentioned a connection earlier, but I wasn't sure what that connection would be :p
  5. Beatnik

    Beatnik

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    MTRR 66 transfers mb12 to MS to generate Metionine. So, if MS is slow, 5mthf+ HCY is slow, and this reaction generates BH2 (then hidroxylated back to bh4 by dhpr) in the direct process and in the reverse process. when 5mthf (ch3) is back to methylene THF (CH2) generates BH4 itself.(1298)

    See if you have MTHFD or MTHFS cause this mutations are critical for BH4 also, not only 677/1298. In order to generate 5mthf you need first generate formyl, and then methenyl, and then methylene THF.

    MTHFR is only responsible for the last step (Ch2 to Ch3 thf (677) and back to ch2 thf(1298)). Not easy, but understandable.

    So i´m against Yasko at this point, 677 mthfd, mthfs are also important for BH4 as far as you can see in the diagram showed. Direct mthfr reaction generates BH2 and inverse reactions generates bh4, but both are important. Dhpr is also important and off course CBS. The whole folate and Methionine cycle are also important, if they are slowed at one point , bh4 is depleted.

    Another key point forgotten by Yasko is Mitochondrial Superoxide Generation, that also limits BH4 but i have no time to explain everything.

    Regards.


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    Last edited: Feb 9, 2014
    roxie60 and helen1 like this.
  6. trollo

    trollo Senior Member

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    Please explain, wich one is the Polymorphism and wich the wild type?? The one into brackets?
  7. trollo

    trollo Senior Member

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    Also Valentjin... what do those C# nd P# mean?
  8. Valentijn

    Valentijn Activity Level: 3

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    C = Control, P = Patient.
  9. trollo

    trollo Senior Member

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    Does the rarity necesarily means 'bad'???
  10. Valentijn

    Valentijn Activity Level: 3

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    Certainly not.
  11. trollo

    trollo Senior Member

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    so basically having one purple or red means nothing?
  12. trollo

    trollo Senior Member

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    Somebody knows where is it possible to know all SNPs for GCH1 and TH genes which are related to reduced dopamine??
  13. Valentijn

    Valentijn Activity Level: 3

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    No, it means that they have rare SNPs on the gene.

    This might potentially be of interest, for example if many ME/CFS patients have a lot of rare SNPs on the same gene.
  14. trollo

    trollo Senior Member

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    ok but there are GCH1 and TH snps that are known to be cause of dopamine defciency, i m interested on them only. Where are them?

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