NK cell deficiency Gene GATA2

[Seven7]

http://www.ncbi.nlm.nih.gov/pubmed?term=23365458

Abstract
Mutations in the transcription factor GATA2 underlie the syndrome of monocytopenia and B- and natural killer (NK)-cell lymphopenia associated with opportunistic infections and cancers. In addition, patients have recurrent and severe viral infections. NK cells play a critical role in mediating antiviral immunity. Human NK cells are thought to mature in a linear fashion, with the CD56(bright) stage preceding terminal maturation to the CD56(dim) stage, considered the most enabled for cytotoxicity. Here we report an NK cell functional defect in GATA2-deficient patients and extend this genetic lesion to what is considered to be the original NK cell-deficient patient. In most cases, GATA2 deficiency is accompanied by a severe reduction in peripheral blood NK cells and marked functional impairment. The NK cells detected in peripheral blood of some GATA2-deficient patients are exclusively of the CD56(dim) subset, which is recapitulated on in vitro NK cell differentiation. In vivo, interferon α treatment increased NK cell number and partially restored function but did not correct the paucity of CD56(bright) cells. Thus, GATA2 is required for the maturation of human NK cells and the maintenance of the CD56(bright) pool in the periphery. Defects in GATA2 are a novel cause of profound NK cell dysfunction.


My results:

GATA2 128199380 rs3803 A or G
AG

GATA2 128199679 rs45598538 A or G
GG

GATA2 128200459 rs2713604 C or T
CC

GATA2 128200534 rs2713603 A or G
AG

GATA2 128201013 rs11717152 A or C
AC

GATA2 128204951 rs2335052 C or T CC


I wonder if my NK issue is genetic? I don't know how to interpret this data pls hlep.

 

[Valentijn]

We're all completely normal for GATA2

 

[merylg]

http://www.ncbi.nlm.nih.gov/pubmed?term=23365458

Abstract
Mutations in the transcription factor GATA2 underlie the syndrome of monocytopenia and B- and natural killer (NK)-cell lymphopenia associated with opportunistic infections and cancers. In addition, patients have recurrent and severe viral infections. NK cells play a critical role in mediating antiviral immunity. Human NK cells are thought to mature in a linear fashion, with the CD56(bright) stage preceding terminal maturation to the CD56(dim) stage, considered the most enabled for cytotoxicity. Here we report an NK cell functional defect in GATA2-deficient patients and extend this genetic lesion to what is considered to be the original NK cell-deficient patient. In most cases, GATA2 deficiency is accompanied by a severe reduction in peripheral blood NK cells and marked functional impairment. The NK cells detected in peripheral blood of some GATA2-deficient patients are exclusively of the CD56(dim) subset, which is recapitulated on in vitro NK cell differentiation. In vivo, interferon α treatment increased NK cell number and partially restored function but did not correct the paucity of CD56(bright) cells. Thus, GATA2 is required for the maturation of human NK cells and the maintenance of the CD56(bright) pool in the periphery. Defects in GATA2 are a novel cause of profound NK cell dysfunction.


My results:

GATA2 128199380 rs3803 A or G
AG

GATA2 128199679 rs45598538 A or G
GG

GATA2 128200459 rs2713604 C or T
CC

GATA2 128200534 rs2713603 A or G
AG

GATA2 128201013 rs11717152 A or C
AC

GATA2 128204951 rs2335052 C or T


I wonder if my NK issue is genetic? I don't know how to interpret this data pls hlep.

Interesting. It's likely no-one knows how to interpret your data yet. Probably a hot topic being studied. If you want to, you can compare your genotype frequency for each snp to results for those who have contributed to openSNP. Just put each 'rs' number into the SEARCH. A page will come up with the number. Then click on the number to see pie charts.

https://opensnp.org/

Do you have your result for the last snp you listed? Also there is one more: rs2860228
eg for rs2860228 I have TT along with only 16% of contributors to openSNP.

 

[NK17]

Thanks @Inester7, are your results from 23andMe?

I'm curious about my results.

I'd think that Prof. Davis @ Stanford will look into this side of our innate immune system, he's doing deep DNA sequencing studies.

 

[Seven7]

@NK17 yes 23and ME
@merylg I updated the last result.

 

[merylg]

@NK17 yes 23and ME
@merylg I updated the last result.

Thanks.
There is one more ie seven snps eg

GATA2, LOC100506995 128209667 rs2860228 C or T
TT

 

[Seven7]

Thanks.
There is one more ie seven snps eg

GATA2, LOC100506995 128209667 rs2860228 C or T
TT

Sorry I dont understand this whole gene thing, what are you saying again???

 

[Critterina]

We're all completely normal for GATA2

@Valentijn ,

I'm not so sure, but I'm still figuring out how to do the research. Please make this a teaching moment!

I go to dbSNP and put in GATA2
http://www.ncbi.nlm.nih.gov/snp/?term=GATA2

I see that there are 87 pages of results and on the first page there are 6 pathogenic alleles.

I click on the first one, to get to the gene viewer where I can put in the rs number or the location (esp. if 23andMe gives an i number)
http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=387906629

Then I go the the "find" part way down the page where the little purple boxes show pathogenic clinical variants and I put in all the position numbers, one at a time.
I find that all the things that 23andMe reports on (or at least that Inester7 listed above) do not have pathogenic alleles, and that there is no data above for the pathogenic alleles.

So, I would conclude that we don't have the data from 23andMe to figure out whether Inester7's NK problems are genetic. More tests showing the pathogenic allele results would be necessary. We just have the wrong data to make a determination.

My questions for you, Valentijn, are:
1. Is there an error in my methodology?
2. Is there an easier way to do this?
3. Is there a problem with my logic?

Thanks!
Critterina

 

[Valentijn]

1. Is there an error in my methodology?

Not with your methodology, and not in this case, but you are assuming that the locations match up between 23andMe and dbSNP - they usually don't. Hence for "i" numbers, you have to find the nearest "rs", find out what the location is on dbSNP, and do the math to figure out where the "i" number should be on dbSNP. I have no idea if it's 23andMe or dbSNP which is off.

2. Is there an easier way to do this?

I'm not completely clear on that part. I'd go to https://www.23andme.com/you/explorer/gene/?gene_name=GATA2 to get the list of the GATA2 SNPs which 23andMe tests for. Then just look up each of those.

3. Is there a problem with my logic?

No, your logic is completely correct. For our 23andMe data, GATA2 is normal. But there are thousands of GATA2 SNPs untested by 23andMe and completely unlabeled with "rs" numbers at all. There definitely could be something going on there, but we have no way to find out. So at that point it becomes a somewhat minor philosophical question which I'm not interested in

But generally speaking, I don't think a specific genetic defect is at all likely in the complete absence of information. And if we're going to start worrying about those, it's never going to end.

 

[anciendaze]

We generally did not show genetic defects prior to some particular illness. This argues against a fundamental problem present from birth. There could certainly be undetected variants which cause milder defects in NK cell function, but at this point I'm thinking we may have no problem with isolated NK cells, only those exposed to biochemical signals.

There is another possible level of complexity since even genes which are present may not be transcribed because of epigenetic control via methylation. Still another level of control could be RNA interference via siRNA. This last would allow DNA to be transcribed into mRNA, but not into proteins. There is a long list of unknowns in the process beyond the presence or absence of a particular allele.

None of this has been researched in any depth for this disease, and it is hard to do useful research when patient cohorts may be dominated by those with a different problem who were chosen by psychological criteria alone. The way around this impasse is to concentrate on those most severely affected, with the most disturbed physiological characteristics. Once you have an answer in those cases you will then know what to look for in less severe cases.

Research on biological aspects of mental illness often involves attempting measurements of picogram quantities of neurotransmitters inside the living brain. This is a recipe for indefinite delay of clinically useful research. In the example of patients with limitations on VO2max which get worse following exercise we are talking about metabolic processes producing grams of lactate in a few minutes.

So why is this currently off official research agendas?

 

[Critterina]

Not with your methodology, and not in the case, but you are assuming that the locations match up between 23andMe and dbSNP - they usually don't. Hence for "i" numbers, you have to find the nearest "rs", find out what the location is on dbSNP, and do the math to figure out where the "i" number should be on dbSNP. I have no idea if it's 23andMe or dbSNP which is off.

Thank you! I did a test and I see the differences. That is just weird.

So, it has always confused me, since the rs numbers don't appear to be in numeric order along the genome how you can tell what is near something else when you only have an i number. Are the rs numbers listed in 23andMe output in location order? How do you know how far is close and how far is far?

Not that long ago the whole Human Genome Project seemed impossible. Although you're not interested in what seems like a philosophical detail, to people who are ill, the hope of discovery of a genetic basis for their condition, with the possibility of an eventual cure, doesn't feel like a minor philosophical point. On that we disagree. And I guess I take exception, respectfully, to your comment that we are all GATA2 normal, as it's based on data from a bunch of non-pathogenic SNPs.

 

[acer2000]

Interesting, according to SNPedia most of the GATA2 genes tested for by 23andMe have associations with increased or decreased risk for heart disease and/or Parkinson's.

 

[Valentijn]

So, it has always confused me, since the rs numbers don't appear to be in numeric order along the genome how you can tell what is near something else when you only have an i number. Are the rs numbers listed in 23andMe output in location order? How do you know how far is close and how far is far?

They're listed in order based on location in the 23andMe online data and raw file.

Not that long ago the whole Human Genome Project seemed impossible. Although you're not interested in what seems like a philosophical detail, to people who are ill, the hope of discovery of a genetic basis for their condition, with the possibility of an eventual cure, doesn't feel like a minor philosophical point. On that we disagree. And I guess I take exception, respectfully, to your comment that we are all GATA2 normal, as it's based on data from a bunch of non-pathogenic SNPs.

Since we don't have the full data yet, it's irrelevant for now. I really do hope we get more data, since it could be extremely helpful. But I'm not going to waste time wondering about the data which we can't access.

 

[Critterina]

They're listed in order based on location in the 23andMe online data and raw file.

Since we don't have the full data yet, it's irrelevant for now. I really do hope we get more data, since it could be extremely helpful. But I'm not going to waste time wondering about the data which we can't access.

Thanks - so close in the list is close on the genome.
I do believe that although "we" can't figure it out, if someone is so inclined, they could find a genetics doctor who sees patients and get their genome tested for the pathogenic alleles. I was looking at the LEPR gene for myself, thinking I might be compound hetero for two recessive mutation that cause early-onset obesity (which did not affect either parent or any of my three siblings). But I got the two genes from my dad, as my mother had none of them. I could still contact the doctor if there are other pathogenic mutations, to see if I have them, but there are other genes to look at first.