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No more Huntington's disease

Also good for other expanding trinucleotide repeat diseases
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So Huntington's chorea is a late-onset inherited disorder with symptoms gradually worsening and leading to dementia.

It's one of a family of diseases caused by an expansion in the number of tandem three-nucleotide repeats - in this case cytosine-adenine-guanine; CAG, in the coding sequence of the huntingtin gene (in which it encodes a string of glutamine residues).
The normal range of repeats is about 10 to 35; the high end of that is at risk and definitely by over 40 there is a strong tendency to develop the disease. Additional repeats over that leads to an earlier onset.
So essentially this locus is 'fragile', being susceptible to mutation. Why is this so?
This sort of repeat is unstable, and can expand or contract during replication. This explains the risk. But why does the repeat exist?
Well, it's been proposed that having more repeats (up to about 40) has a positive effect on intelligence (link), so there is some selection for the 'at risk' state.
However, I suggest that the existence of the repeat as such is simply a result of the evolution of the site by mutation - the beneficial effect is actually due to the string of glutamines.

So. Let us assume that at some point in the future scar- less genetic engineering in humans becomes possible. This looks like it might actually be feasible, and may eventually be low-risk and accepted enough to be commonplace.

There are actually two codons which encode glutamine; CAG and CAA. It's highly likely that CAA could be substituted for some of the CAG codons without impacting function, and this should reduce mutation.
I don't claim to know enough to specify the best way to avoid repeat expansion or slippage. Maybe it is alternation, maybe it is a semi-random distribution of the two. Furthermore- it is, I believe, likely that the requirement for glutamine isn't completely stringent and other amino acids could also be substituted at least a fraction of the sites - Aspartic acid is in the 'highly conserved' category and has two codons: GAC and GAT - judicious use of these could further disrupt mispairing. Experimentation in animal models could determine this.

Therefore it may be possible to 'fix' this fragile locus to more reliably retain the most beneficial length while avoiding the risk of disease in descendants.

Loris, May 10 2019

Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence https://www.ncbi.nl...rticles/PMC6013750/
scientific paper. [Loris, May 10 2019]

[link]






       This could be attempted (sort of) now or in a few years using CRISPR. It would be an easy fix for a human oocyte; it would also be fixable in a whole person, but treating a large enough proportion of the relevant cells (or all cells) would be difficult. My own company is also working on an editing technology that could do this.   

       I wouldn't trust the purported link between repeat number and intelligence - it's probably spurious. And I agree, replacing some CAG codons with CAA would prevent triplet expansion and probably have no adverse consequences.
MaxwellBuchanan, May 10 2019
  

       //This could be attempted (sort of) now or in a few years using CRISPR.//   

       CRISPR isn't fit for this purpose yet. Too many off-target mutations.
And yes, the germ-line is the ideal point of action.
  

       //I wouldn't trust the purported link between repeat number and intelligence - it's probably spurious//   

       It might be, but please refer back to the cautious language in which I couched the statement.
It doesn't really matter. Presumably function requires at least a short run of glutamine (if not, trim to one; problem solved!), so we really just need a massive trial to determine the optimum number, and then nail that down in the genome.
Loris, May 10 2019
  

       What's really needed is some very fast memory editor so people wouldn't remember they lent money to me.   

       Weird, I'm sure I had fiver..must be here somewhere
not_morrison_rm, May 10 2019
  

       // My own company is also working on an editing technology that could do this. //   

       "My own company has bought one of those nifty high-speed drill thingies in the weekly discount sale at Lidl and we are looking round for something to try it on."   

       // Too many off-target mutations. And yes, the germ-line is the ideal point of action. //   

       <Obligatory Blade Runner Reference>   

       "We've already tried it. Ethyl methane sulfonate is an alkylating agent and a potent mutagen."   

       </OBRR>
8th of 7, May 10 2019
  

       //Too many off-target mutations.// Exactly. I am waiting for it to kill a few people.   

       // germ-line is the ideal point of action// Yes and no. The people who are most upset about Huntington's are people who are already multicellular. Genome editing needs to work for grown-ups.   

       //weekly discount sale at Lidl// Harrumf. If you get Huntington's, don't come running to me.
MaxwellBuchanan, May 10 2019
  

       //The people who are most upset about Huntington's are people who are already multicellular.//   

       I suppose that's true, but I was thinking in terms of my proposed preventative treatment.
If you're trying to expunge the progression of Huntingdon's chorea in an adult's brain, you presumably 'just' need to trim out excess repeats in the appropriate cells. Trying to prevent those repeats from ever expanding again over multiple generations is unnecessary complexity in somatic tissue.
Loris, May 10 2019
  

       Life would be so much simpler if we were all single- celled organisms.
RayfordSteele, May 11 2019
  

       Well we used to be, but then some wise-guy eukaryote said "Listen! I have an idea ..."
pertinax, May 11 2019
  
      
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