Homozygous Mutations in NDUFS7: What Does This Mean?

Gamboa

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Hi all,

I have some homozygous mutations in 4 SNP's in the NDUFS7 gene but can't find out if it means I have a mitochondrial disease or not. The 4 in question are NDUFS7 rs1142530, rs7258846, rs11666067 and rs2074895.

NDUFS7 is NADH-ubiquinone oxidoreductase Fe-S protein 7, and is also called NADH-coenzyme Q reductase. It is 1 of over 40 subunits of the mitochondrial respiratory chain complex 1. Having mutations in this gene apparently causes Leigh Syndrome, a fatal childhood mitochondrial disease and Mitochondrial Complex 1 Deficiency (MT-C1D). I have looked up these diseases and they look very extreme and I am not as sick as the people with these diseases are, unless there are milder forms of MT-C1D.

I have had blood and urine metabolomic tests done at Nutrichem and it indicates mitochondrial problems and an abnormal Kreb's Cycle. I have done the 2 day CPET protocols and it indicated that I have an inability to produce energy properly and have abnormal lactic acid production, again indicating mitochondrial issues. I have had SPEC scans of my brain which show hypoperfusion. I have had TILT table testing with accompanying cardiac alpha and beta adrenergic sensitivity and activity testing. These showed that I have a decreased intrinsic heart rate, inability to achieve maximum target heart rate and a decreased alpha sensitivity test. I also have orthostatic hypotension. All of these could point to mitochondrial problems.

I know they suspect ( or do they know for sure?) mitochondrial problems in ME/CFS but where does one differentiate that from an actual mitochondrial disorder? Do I not have ME/CFS after all ?

Has anyone else doing 23and me had similar results? Please help.
 

Sea

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I also am homozygous for all 4 snps. I haven't researched them much, but given that their prevalence is all 44% I would make 2 comments:
1. They are probably inherited as a package.
2. They are so common that I doubt there would be a large effect from them
 

helen1

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I am homozygous for NDUFS7 rs7254913 and hetero for three of the NDUFS8. My doc told me that they may indeed significantly impact mito function, via respiratory chain complex 1.

She recommends NADH and ubiquinol supplementation as more effective for us than plain CoQ10 and B3. She also says this is a "newly studied gene defect".
 

Gamboa

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I also am homozygous for all 4 snps. I haven't researched them much, but given that their prevalence is all 44% I would make 2 comments:
1. They are probably inherited as a package.
2. They are so common that I doubt there would be a large effect from them
Where did you find the the prevalence rate? I can't seem to find much information about it at all.
 

Sea

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Where did you find the the prevalence rate? I can't seem to find much information about it at all.
dbSNP

eg http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs1142530

Under the heading Allele at the top of the page it has 0.444/997 for the minor allele frequency. This means the minor allele was seen with a frequency of 44.4% in the 1000 genome database and 997 times in total (a heterozygote is one count of the minor allele and a homozygote is 2)

From the browse raw data page on 23andme you can search by gene or rs number. The little + signs to the left of the snps are a drop down menu with links to dbSNP and Google Scholar.

OMIM is a good resource for information about gene effects too

http://ghr.nlm.nih.gov/gene/NDUFS7/show/OMIM
 

Sea

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I am homozygous for NDUFS7 rs7254913 and hetero for three of the NDUFS8. My doc told me that they may indeed significantly impact mito function, via respiratory chain complex 1.

She recommends NADH and ubiquinol supplementation as more effective for us than plain CoQ10 and B3. She also says this is a "newly studied gene defect".
There are certainly snps in these genes that are important in mitochondrial disorders but that doesn't mean that all snps on these genes will have mitochondrial effects. It is not enough to say I have a defect on this gene. You have to look at the research to know what effect, if any, your particular snp has. 23andme don't necessarily test the ones that the research talks about.
 

Gamboa

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dbSNP

eg http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs1142530

Under the heading Allele at the top of the page it has 0.444/997 for the minor allele frequency. This means the minor allele was seen with a frequency of 44.4% in the 1000 genome database and 997 times in total (a heterozygote is one count of the minor allele and a homozygote is 2)

From the browse raw data page on 23andme you can search by gene or rs number. The little + signs to the left of the snps are a drop down menu with links to dbSNP and Google Scholar.

OMIM is a good resource for information about gene effects too

http://ghr.nlm.nih.gov/gene/NDUFS7/show/OMIM
Thanks Sea.

I have bad brain fog right now and couldn't understand the first reference at all. If having one minor allele had a frequency of 44%, what is the frequency of having 4 with a homozygous minor allele? ( I don't even know how to phrase this).

Do you now if anyone in the ME field has researched any of this?
 

Sea

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Thanks Sea.

I have bad brain fog right now and couldn't understand the first reference at all. If having one minor allele had a frequency of 44%, what is the frequency of having 4 with a homozygous minor allele? ( I don't even know how to phrase this).

Do you now if anyone in the ME field has researched any of this?
No it's not 44% for one minor allele. The 1000 genome database they use means they're looking at around 2000 alleles for this snp (2 from each person). In that sample they found the minor allele 44% of the time, or 997 times. Some of those would be heterozygous and some would be homozygous.

If you look lower on the dbSNP page you can find frequencies for hetero and homo for different ethnicities with coloured bars and percentages noted.

Some snps are likely inherited as a package deal, but you can only find that out by researching further. It's not easy info to find. Not all snps are well researched. I don't know if these ones have been looked into in ME.

Because these 4 snps have a very similar prevalence it is very likely they are inherited as a group. If that were the case then the chance of having all 4 would be about the same as the chance of having one of them
 

Valentijn

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I have bad brain fog right now and couldn't understand the first reference at all. If having one minor allele had a frequency of 44%, what is the frequency of having 4 with a homozygous minor allele? ( I don't even know how to phrase this).
Minor Allele Frequency (MAF) can be used to determine approximate prevalence of heterozygous and homozygous genotypes. If MAF is .44, then you multiply .44 x .44 for homozygous frequency, which comes out to 19.36% prevalance.

So about 1 in 5 people have that genotype, meaning it's common as dirt, and has about 0 chance of being pathogenic. Usually effect size for such common SNPs is small, if there's any effect at all. And you can't trust the various sites which process these results, as they are often wrong and don't provide links to the research supporting their claims.

Regarding the frequency of having 4, as @Sea indicated, it's impossible to guess. It depends on whether they are all inherited independently or together. If all 4 were usually inherited together, then having the homozygous version of all 4 would be just as common as having the homozygous version of a single one.

Basically if it's a common genotype, then it usually isn't important. There are some rare exceptions, but not many. Hence I find rare SNPs to be far more interesting than most of the crap on Yasko's little list, or other similar lists from various sites.
 

Valentijn

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I have some homozygous mutations in 4 SNP's in the NDUFS7 gene but can't find out if it means I have a mitochondrial disease or not. The 4 in question are NDUFS7 rs1142530, rs7258846, rs11666067 and rs2074895.
A few more notes: all 4 of these SNPs are inherited together about 99% of the time. There is tiny variation between a couple of them, but it's completely normal to get all 4 as homozygous - just as normal as getting 1 as homozygous.

NDUFS7 (rs1142530) is almost certainly not involved in Leigh's syndrome in any significant amount. An "old" case study of two sisters with Leigh Syndrome identified that they have this missense mutation. But so do 20% of all people, almost none of whom have Leigh Syndrome. The study was done prior to prevalence of different genotypes being known, so investigators would just look for something that seems odd, which might be connected to the disease, and publish.

But if a proper study were done now, it would probably show that the there's no difference in allele prevalence between cases and controls. Hence the results of that study were clearly a false positive - there is simply no way that a minor allele with 44% prevalence (max is 49.9%) could be pathogenic.

I've also looked around for other research regarding that SNP, and there isn't any. So it's looking 100% harmless currently.
 

Gamboa

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A few more notes: all 4 of these SNPs are inherited together about 99% of the time. There is tiny variation between a couple of them, but it's completely normal to get all 4 as homozygous - just as normal as getting 1 as homozygous.

NDUFS7 (rs1142530) is almost certainly not involved in Leigh's syndrome in any significant amount. An "old" case study of two sisters with Leigh Syndrome identified that they have this missense mutation. But so do 20% of all people, almost none of whom have Leigh Syndrome. The study was done prior to prevalence of different genotypes being known, so investigators would just look for something that seems odd, which might be connected to the disease, and publish.

But if a proper study were done now, it would probably show that the there's no difference in allele prevalence between cases and controls. Hence the results of that study were clearly a false positive - there is simply no way that a minor allele with 44% prevalence (max is 49.9%) could be pathogenic.

I've also looked around for other research regarding that SNP, and there isn't any. So it's looking 100% harmless currently.
That's good news. So I am back to having ME/CFS after all, and not a mitochondrial disease. :)
Every now and then I look into other possible diagnoses, something treatable or curable, but it just doesn't work out. I'll just have to be patient and keep waiting for something to happen in the ME/CFS world.
 

Valentijn

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Every now and then I look into other possible diagnoses, something treatable or curable, but it just doesn't work out. I'll just have to be patient and keep waiting for something to happen in the ME/CFS world.
Maybe you've already found it, but I've got a nice little download at http://http://sourceforge.net/projects/analyzemygenes/ which will pull out very rare results from your 23andMe file. Results starting with an "i" instead of "rs" are often (but not always) pathogenic to some degree, and the rarest results also usually include a few missense mutations.
 

Tunguska

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I also found out through the Sterling app I have at least 2 NDUFS7 homozygous mutations. Coincidentally a few weeks before I started taking ubiquinol, 200-300mg/day and noticed a bit difference in alertness. But really that could be for any reason. I have chronic fatigue made worse directly or indirectly by fluoroquinolones.
 
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That's good news. So I am back to having ME/CFS after all, and not a mitochondrial disease. :)
Every now and then I look into other possible diagnoses, something treatable or curable, but it just doesn't work out. I'll just have to be patient and keep waiting for something to happen in the ME/CFS world.
Been there so many times :)
 
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I got three NDUFS7 +/+ mutations (rs2332496, rs1142530, rs7258846) and also the NDUF3 +/+ (rs4147730), I’m also +/- on three off the NDUFS8.
Also some of the of the COMT and MTHFR ones.
I also found out that I'm deficient in some B vitamins: especially B1, B7, B3 and B5
 
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Maybe you've already found it, but I've got a nice little download at http://http://sourceforge.net/projects/analyzemygenes/ which will pull out very rare results from your 23andMe file. Results starting with an "i" instead of "rs" are often (but not always) pathogenic to some degree, and the rarest results also usually include a few missense mutations.
How do you work the site: sourceforge.net/projects/analyzemygenes/ ?? I downloaded it, but how do I start to use it or extract it?? Sorry but I'm not too computer savvy.
 
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SNPs in NDUFS7 (NADH dehydrogenase) is responsible for electron transport so it will cause mitochondrial (energy) issues since you will not produce enough ATP. It helps turn NADH into NAD+.



The cofactor for this gene is a iron-sulfur cluster. Have you been diagnosed with anemia?

Wondering if you have any SUOX SNPs? Since SUOX turns sulfite into sulfate, a SNP here will leave you with less sulfate and therefor less iron-sulfate.
 

Valentijn

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How do you work the site: sourceforge.net/projects/analyzemygenes/ ?? I downloaded it, but how do I start to use it or extract it?? Sorry but I'm not too computer savvy.
You'll need to go to where it downloaded, click on the folder, and there should be an option somewhere (top left?) for extracting the folder. Then you can choose to put it somewhere easy when it extracts, such as on your desktop.

Then you can run the genes.jar file, though your 23andMe file will also need to be downloaded and extracted first.
 

grapes

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For me, it does appear that my three homozygous NDUFS7 mutations are now expressing themselves, resulting in some pretty bad mito Chronic Fatigue. Yes, it's a guess that they are now active mutations, but I have strong reasons to believe so.

For one, my Organic Acids Tests (OAT) have issues that constantly point to the need for more CoQ10. Yet, I've seen evidence that any ubiquinone Coq10 that I've taken hasn't been helping me, even higher doses of 600 mg. But when I moved to ubiquinol, I get some relief. i.e. this gene when working right is supposed to help break B3 down to NAD+/NADH, and it's the latter what helps CoQ10 break down for use.

Second, I've begun to see great relief from my fatigue by taking straight NADH with CoQ10...much more relief than when I was taking the precursor to NAD (which may not help if I'm not breaking it down.) I've still a long way to go, though.
 

alicec

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it does appear that my three homozygous NDUFS7 mutations are now expressing themselves, resulting in some pretty bad mito Chronic Fatigue. Yes, it's a guess that they are now active mutations
You misunderstand how SNPs work. They are part of the gene structure. If the gene is expressed then so is the SNP. From birth to death this does not change.

Your symptoms could be worsening for all kinds of reasons