C9orf72 - a major cause of MND?

[PaulaF]

Expansions in the C9orf72 gene have been linked to 40% of familial ALS and 9% of sporadic ALS. Of the 170,000 people in the UK who are likely to develop ALS over their lifetimes, this suggests around 20,000 cases will be linked to C9orf72.

Does this mean C9orf72 expansions are the cause of the ALS? Not necessarily, as we can’t discount the possibilities that the ALS is causing the expansions (rather than the other way round) or that something else is causing both (but that neither significantly affects the other). It might be that expansions are just a sign/marker of ALS, rather than being its cause?

Several chromosome 9 point mutations (e.g. rs3849942 and rs2814707) are linked to both the expansions and the disease. If we multiply their given risk scores by their population frequencies, we can estimate up to 67,000 people in the UK will develop ALS linked to these mutations, which explains three times as many cases as the expansions do and increases the estimate to up to 40% of ALS cases in the UK being linked to chromosome 9.

Intriguingly, none of these point mutations are on the C9orf72 gene itself, but all are located just before it. Perhaps these advance mutations can provide a key to better understanding MND and potential treatments for it?

Hopefully, more to follow.

[Ellie]

Jen70400 A warm welcome to the forum Jen, thanks for posting. xx

[PaulaF]

^{your post looks like you copied it from somewhere ? Please discuss with your neurologist because tt doesn’t seem a reliable source. There is a lot in it that is counter to what my neurologist and neurogenetist say}

Thanks for replying, Jen.
It's my own prose, but the basic information was of course obtained from the internet.

From what I have read, c9orf72 expansions are found in a substantial minority of familial ALS cases and a small minority of sporadic ALS cases. My understanding is that roughly 1 in 400 people develop ALS during in their lifetimes. I just came to my figures by doing the maths.

Here are the 7 individual genetic position results in chromosome 9 reported in various studies to have the strongest statistical relationships to ALS incidence:
rs147211831 ALS risk allele A, genomic location 9:27,436,086
rs139185008 ALS risk allele C, genomic location 9:27,491,944
rs2814707 ALS risk allele T, genomic location 9:27,536,399
rs3849942 ALS risk allele T , genomic location 9:27,543,283
rs3849943 ALS risk allele C, genomic location 9:27,543,384
rs147599399 ALS risk allele G, genomic location 9:27,543,631
rs10967976 ALS risk allele G, genomic location 9:27,544,945
Each of these risk alleles is reported to be associated with odds ratios of between 1.076 and 1.39. Again, you just need to factor in the reported frequencies in the general population and do the maths.
The c9orf72 gene is located on chromosome 9 between 9:27,546,546 and 9:27,573,866. As you can see, each of the ALS risk alleles are positioned just before the c9orf72 gene and are associated with expansions towards the end of the gene which occur between positions 9:27,573,525 and 9:27,573,542.

I suppose some of this might be a little out, but much of it was taken from published academic studies. It would be interesting to find out which things are counter to what your neurologist and neurogeneticist say, so I could check further. I'm keen to learn!

[PaulaF]

Well to start the c9 orf72 mutation is not acquired during life. It is part of a carrier’s DNA and present at conception- usually inherited , occasionally a spontaneous mutation during conception ( called de nova). Gene expression can change environmentally but one’s DNA does not without gene editing like CRISPR.

I'm not sure about this. Depienne's paper in AJHG volume 108 references somatic instability in repeat expansions, with each cell division being associated with a risk of error during DNA replication (i) due to slippage of DNA polymerase while replicating repetitive DNA sequences, (ii) amplified by the ability of some repeats to form stable folded structures such as hairpins, stem-loops, cruciform, and/or tetraplexes, and (iii) with evidence of instability as a result of DNA mismatch repair processes. The degree of mosaicism varies with existing expansion size and age, and can show large variations in different tissues, which would seem impossible if the number of repeats were fixed at conception.
A fixed size would also seem to contradict evidence from a family member with an intermediate c9orf72 expansion who had a set of several test results each showing a different repeat number (between 8 and 20).
c9orf72 expansion is not really a mutation, but a repeat of an already-existing short sequence of DNA.

I have been told that c9 is the cause of my ALS.
c9 is more prevalent in some populations than others. In the UK I think it accounts for 15 percent maybe higher in the North. In the US it is about 10 percent or a little higher. In Finland where it is believed to have started it is about 40 percent of ALS. It is much lower in Asia

So my approximation of 12% in the UK is probably not too far off.

testing for this is not usually done by those risk allelles.

That's right, testing only counts the number of repeats, not how many people have ALS.
Some people with expansions do not get ALS, but a different disease (FTD) instead. Others do not get any disease at all. And some people get c9orf72 ALS without having the full expansion picked up by the test.

The risk alleles indicate something different - the heightened risk of getting ALS as a consequence of having individual c9 mutations. These yield an estimate that c9 mutations are linked to a significantly larger number of ALS cases than the PCR and Southern blot repeat tests indicate. That was my first point.

And the fact that all of the highest-risk mutations arise slightly upstream of the c9orf72 gene (rather than in it) throws open the possibility that the root cause of much of ALS lies within chromosome 9, but outside of the c9orf72 gene itself.

I am not disputing anything as such, just wondering whether this kind of lateral thinking could help in coming up with a potential treatment.

[Drumond30]

Jen70400 could you point me to the trial you referenced above that published its failure on Monday please.
We are currently getting my Dad tested, although there is no history in our family, my Dad's sister has FTD which we didn't know was a relatable condition until my Dad developed MND. Seems we are also going down the rabbit hole of genetics, which is utterly terrifying. I am trying to educate myself as much as possible.

[PaulaF]

C9 is an unstable expansion. That doesn’t mean that it is not either expanded at birth or not. I read the paper it does not say otherwise Yes you can have an expansion and not get a disease but that is rare if you live a long life. Yes you can have FTD and some other manifestations. No if you do not have an expansion by proper pcr testing your ALS is not c9orf72 ALS.

c9orf72was discovered in late 2011. Since then many many researchers have been working on it. Thousands of papers have been written. Treatments have been developed. The most promising just announced its failure Monday.

are there other mutations on chromosome 9 that people get? Of course. Have all the ones you list been deemed pathological? I don’t think so but if they are not located at open reading frame 72 they are not c9orf72 which was your title of this thread. There is a website of ALS associated mutations by Professor Al Chalabi and Kings. I can’t find it. Maybe someone else can direct you. We clearly disagree. I encourage you again to speak to your MND neurologist and geneticist about your ideas. Good luck

Jen, I can’t see that we’re disagreeing about anything really other than terminology (whether something can be called c9orf72 ALS or not). And I’m not really expressing ideas, just pointing out the fact that ALS, c9orf72 repeat expansions and allelic mutations located just before the c9orf72 gene all correlate with each other. We don’t know exactly how they relate to each other, and it could be useful to find out.

I would suggest continuing to consider anything that might be relevant to our understanding. It doesn't seem gainful to exclude considering evidence about people with ALS simply because their number of repeats is one short of being officially classified an expansion, because their doctor hasn’t sent them for a particular category of test yet, or because their related mutations sit just before the start of the c9orf72 gene rather than actually in it. We need to remember that c9orf72 is not a stand-alone gene, ring-fenced from the rest of the genome – it interacts with other genes, and the workings of other genes (particularly those adjacent to it) can affect its function.

I’ll try to post some further information about this, hoping it might elicit useful observations from other people. As someone who clearly has a lot of knowledge about the subject, I am hoping you might continue to engage with this discussion.

[PaulaF]

https://investors.biogen.com/news-releases/news-release-details/biogen-and-ionis-announce-topline-phase-1-study-results?fbclid=IwAR2prtg4-sb8BwORy4MaSnbi9rRNA348DSet3_LlBfaE5eSi3VnBf88CkSs

Disappointing, as this seemed a promising development.
Their conclusion that the results do not support the hypothesis that the mechanisms of disease were caused by toxicity associated with the repeat suggests we should still be exploring other avenues, I feel.
Although perhaps refinements to tests like this might yield better results in future.

[PaulaF]

As c9orf72 ALS affects the brain and/or spinal cord, it is perhaps unsurprising that allelic mutations associated with ALS located adjacent to the c9orf72 gene are also associated with FTD and other brain conditions. Possibly more surprising are the associations of these same mutations (e.g. rs2814707) with lupus, rheumatoid arthritis and in particular type 1 diabetes.

Although perhaps associations with autoimmune conditions should not be so unexpected, as most of these mutations are in an uncharacterised area of chromosome 9 located immediately between the c9orf72 gene and the IFNK gene that is involved in immune and inflammatory responses. And it further matches that c9orf72 is the only type of ALS in which there are reported to be substantial elevations in the inflammatory markers CRP and TNF alpha. (I can provide study references for this if anyone would like.)

Could this suggest that c9-related ALS might have an auto-immune element like the other diseases to which it is genetically associated? And do we know the extent to which auto-immune medications been tested on it?

[PaulaF]

https://investors.biogen.com/news-releases/news-release-details/biogen-and-ionis-announce-topline-phase-1-study-results?fbclid=IwAR2prtg4-sb8BwORy4MaSnbi9rRNA348DSet3_LlBfaE5eSi3VnBf88CkSs

With the abandonment of this trial, doubts may be surfacing about toxic repeats being the prime driver of chromosome 9-related MND, but hopefully research in this area will continue apace.

Before we knew much about these repeats, research seemed to be leading towards defects in the pathway between the IFNK inflammatory gene and the c9orf72 brain protein gene being a significant factor and affecting perhaps a wider pool of people. Pharmaceutical companies and academics have invested a lot of money and professional standing on biogenetics approaches, so I am hoping it will not take them too long to perhaps re-widen their focus a bit.

With a MND diagnosis in my case and a family member having both intermediate repeat expansions and the main risk alleles homozygously, I have a personal interest in this; but as I’m not sure others really want to hear about it, I am inclined to stop at this point unless something major comes up.

[PaulaF]

Good recent research paper from Reus et al in Translational Psychiatry identifying 3 genetic variants that explain virtually all c9orf72 expansions.

22% people with 2 of the variants had the expansions, and these variants were associated with disease even in the absence of expansions. Predictably, a member of my family has all 3.

The paper notes that as few as 4 repeats can interfere with DNA replication, and that expansions can occur both during parent-offspring transmission and within tissues.

Most interesting is key variant rs117204439-C which is located at the end of the CTAGE12p gene just before the c9orf72 gene. This is a T cell-associated gene expressing mainly in the brain and pituitary gland, which might provide clues to inflammatory and neurotransmission processes in this variety of MND.

[Johnny5]

10% are familial, but the number of genes involved has grown substantially in the last 12 years.

[PaulaF]

10% are familial, but the number of genes involved has grown substantially in the last 12 years.

Yes, thèy are finding more and more that genetic factors are a major cause.

I think the 10% familial figure can be a little misleading, as this only counts the people where the genetic weakness has been firmly evidenced by MND in another family member. There are probably other people with genetic weaknesses that just haven't been triggered as MND. Familial is not the same as hereditable.

[Drumond30]

Does this mean there is no hope for those of us who have a family member with MND and that is most likely genetic they just haven't found the gene yet? We are waiting on results coming back from my Dad, whilst there is no family history of MND or FTD before my Dad's generation, my Aunt has FTD. Nothing else so far on that line but I'm not hopeful this won't come back as genetic.

[PaulaF]

Does this mean there is no hope for those of us who have a family member with MND and that is most likely genetic they just haven't found the gene yet? We are waiting on results coming back from my Dad, whilst there is no family history of MND or FTD before my Dad's generation, my Aunt has FTD. Nothing else so far on that line but I'm not hopeful this won't come back as genetic.

No, there is hope. They are finding only in the last couple of years that many of these genes link to each other, and you might need a combination of them plus an environmental trigger to actually get the disease. Not everyone in families gets the same problem.
For example, a mutation in the CTAGE12p gene has been linked to C9orf72 gene expansions, which have in turn been linked with reduced expression from the SOD1 gene.
Understanding this better will help them come up with treatments that could block the actions of some of the harmful mutations and/or boost the actions of the good genes.

[PaulaF]

Does this mean there is no hope for those of us who have a family member with MND and that is most likely genetic they just haven't found the gene yet? We are waiting on results coming back from my Dad, whilst there is no family history of MND or FTD before my Dad's generation, my Aunt has FTD. Nothing else so far on that line but I'm not hopeful this won't come back as genetic.

When did your Dad take the test?
in my case, the NHS consultant wanted to discuss this first (3 month wait to next appointment), so paid for one privately - they said it will take up to 2 months for the results.