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May have found first genetic mitochondrial screw up.

Discussion in 'Genetic Testing and SNPs' started by nanonug, Mar 9, 2018.

  1. nanonug

    nanonug Senior Member

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    This is going to get a little technical so bear with me, please.

    While trying to understand the biochemistry behind ketogenesis diets, I stumbled upon a condition known as Carnitine Palmitoyltransferase II Deficiency. It is associated with genetic variations in the CPT2 gene. I decided to check my CPT2 gene on ENLIS, from 23andMe data, and found several variations, all of them homozygous.

    Two of the variations found were associated with protein coding and the rest are introns for which absolutely no information is available. The two protein coding are rs1799821 and rs1799822. The latter one has a minor allele frequency of ~16% and is considered benign/likely benign. The first one, on the other hand, has a "risk factor" label attached although with an allele frequency of ~48%. Homozygosity has certainly lower frequency but I don't know how much.

    Focusing on rs1799821 (CPT2 V368I) homozygous mutation ("bad" allele is "A"), I found an interesting paper entitled "Abbreviated Half-Lives and Impaired Fuel Utilization in Carnitine Palmitoyltransferase II Variant Fibroblasts." In this paper, one may read the following:

    Reduction of mitochondrial membrane potential
    We assessed the mitochondrial membrane potential (ΔΨm) using the cationic lipophilic probe JC-1. Normal mitochondria with a high ΔΨm appear red following aggregation of JC-1, which emits red fluorescence at ~590 nm. Following mitochondrial depolarization with a low ΔΨm, the JC-1 dye remains in its monomeric form, thereby emitting relatively more green (~525 nm) fluorescence [32]. We observed an increase of green fluorescence and a reduction of red fluorescence in the mitochondria of fibroblasts from patients with p.V368I (homozygous) and p.F352C (heterozygous) + p.V368I (homozygous) variants compared with mitochondria from control fibroblasts at both 37°C (Fig. 4A, B, C) and 41°C (Fig. 4D, E, F). Mitochondrial depolarization is a marker of mitochondrial dysfunction and precedes ATP depletion, so the data indicate a relatively low ΔΨm of patient fibroblasts at 37°C and an enhanced decrease in ΔΨm under heat-stress conditions at 41°C.

    In essence, being homozygous for CPT2 V368I (rs1799821) leads to decreased membrane potential. This membrane potential (literally a difference in voltage) is fundamental for the creation of ATP from ADP and inorganic phosphate. Less membrane potential leads to lower synthesis of ATP from ADP. This is even worse if one runs a fever.
     
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  2. aquariusgirl

    aquariusgirl Senior Member

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    Ok, I looked at CPT2 on ENlis & I only have one SNP on an intron & my mom has nothing. Huh?

    Does this even make any sense?

    my mom & I are G/G for 1799821 & both are T/T for 2229291
     
    Last edited: Mar 11, 2018
  3. pattismith

    pattismith Senior Member

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    I am only heterozygous for rs1799821 but my mother is homozygous mutated.

    According to the study, this mutation decreases CPT II activity only if associated to the other mutation F352C:

    "The CPT II activity of control fibroblasts was 0.28 ± 0.05 nmol/min/mg protein (n = 5),
    that of p.V368I (homozygous) was 0.27 ± 0.05 nmol/min/mg protein (n = 5),
    p.F352C (homozygous) was 0.18 ± 0.05 nmol/min/mg protein (n = 5),
    and p.F352C + p.V368I was 0.15 ± 0.05 nmol/min/mg protein (n = 5)"

    ( F352C is rs2229291, I am homozygous normal for this one and so my mother is)
     
    Last edited: Mar 10, 2018
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  4. nanonug

    nanonug Senior Member

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    ENLIS (to my knowledge) only shows variations. If it doesn't show anything, either there's no data available or there is no variation.
     
  5. nanonug

    nanonug Senior Member

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    That's true, but according to the study (which I quoted), it is enough to be homozygous for V368I to affect mitochondrial membrane potential. A reduced membrane potential leads to reduced synthesis of ATP. This is independent of the effect on carnitine palmitoyltransferase II, which may very well be none.

    Unfortunately, I don't have rs2229291 on my 23andMe data.
     
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  6. pattismith

    pattismith Senior Member

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    So you may have done the test more than a year ago, when they changed their plateform ...

    Yes they say that, but didn't give any precise datas so I am a bit septical.
    Are you sure the deffect in mitochondrial depolarisation observed has no link with CPT2 impairment?
     
  7. nanonug

    nanonug Senior Member

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    Yeap!

    Fair enough!

    I am most definitely not sure! Based on my reading, the paper suggests they are separable but as you correctly asserted they don't give enough data to make a more forceful determination. I would also like to see these results validated from a different source.
     
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