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jubears09 t1_ja8qpu7 wrote

Yes; the best studied mechanism for this is cellular interference.

PCDH19 is the classic human disease example. It's a protocadherin (cell surface protein that affects migration, signaling, etc) on the X chromosome. When both normal and abnormal PCDH19 is present (XX heterozygotes) affected individuals have epilepsy and developmental delay because neurons with different variants behave differently and have trouble forming networks with each other. XY males, regardless of whether there is a mutant or wt allele are normal. XXY males or mosaic males have the same phenotype as heterozygous females.

This is an illustration: https://www.ncbi.nlm.nih.gov/books/NBK98182/figure/depienne.f4/

EFNB1 is another example: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605834/

OLD paper postulating this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1686061/

Edit: I know you said you're not interested in sex chromosomes, but this disease mechanism applies just as easily to autosomal genes. We can predict based on males that a true mutant homozygote would be unaffected while a compound heterozygote would be affected.

The problem with finding an autosomal example is being homozygous outside of a consanguinous situation is exceedingly improbable. Not only do both alleles need to develop a disease causing mutation, but they need to mutate in the same way by chance. Most recessive diseases we see are caused by a compound heterozygous state; which while not wild type, it also not homozygous.

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AbouBenAdhem t1_ja95g5v wrote

So if I understand the abstract from the PCDH19 link, the problem isn’t heterozygosity on a cellular level, so much as random X-inactivation causing regions of incompatible homozygous (hemizygous?) cells. Is that correct?

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jubears09 t1_ja9kp9y wrote

Sort of. Protocadherins are like address codes in the developing brain. So the problem is having 2 different sets of instructions for migrating neurons. Hence heterozygotes have disease and homozygotes (even if mutant) are normal. even if co-expressed absent mosiacism the prediction would be disease. However, for reasons I mentioned in the original post human examples would be hard to find because the event of 2 identical yet independent mutations would be highly improbable.

In diseases with recurrent mutations there is usually a mechanistic reason (Gain of function in achondroplasia) that wouldn't apply here.

Here is an even older paper describing this before we found any examples.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1686061/

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Droopy1592 t1_jaa720x wrote

This is so damn interesting. I would have never seen anything like this in my normal studies. I never would have thought heterozygous could be worse.

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wheatgrass_feetgrass t1_ja9f6vn wrote

This is how I interpreted it as well. The issue is more of the mosiaic distribution of the different tissue. It ends up patchy like a tortoise shell cat's fur.

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Germanofthebored t1_ja9gy6e wrote

Oh no, I thought (and taught) that one of the two X chromosomes gets packed away in the Barr body. Do both X chromosomes add to the exogne of the cell, or is the problem an interaction between cells?

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za419 t1_ja9jkkw wrote

The problem is in the interaction. If you imagine the "normal" X chromosome (let's call it N), and the "bad" X chromosome (B), then a network of entirely B cells or entirely N cells works fine, since they're all on a standard "protocol" if you will.

However, if you undergo X inactivation in an individual that has BN genetics (one copy of each), then you get some clusters of cells with each type - And at the interface between B and N you get weird, glitchy behavior that can cause symptoms like seizure because they aren't quite fully compatible with one another.

At least, assuming I understood correctly.

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MaygeKyatt t1_jaaccl4 wrote

It’s just a problem with the interactions between cells, it sounds like. You’re correct, X Inactivation virtually completely disables one X chromosome, it just happens after cells have divided several times, so some clusters of the developing embryo have one X chromosome while other clusters have the other chromosome.

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lituranga t1_ja9kmon wrote

That’s not true, there are many AR conditions with common pathogenic carrier mutations which mean that many affected individuals are absolutely homozygous without any consanguinity.

It’s not exceedingly improbable at all. Examples off top of my head are delta f 508 for Cystic fibrosis, all the ashkenazi Jewish common AR conditions, SMA, sickle cell disease, alpha thal, beta thal, and I’ve personally seen many patients with other disorders who are affected and homozygous for same pathogenic variant.

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jubears09 t1_ja9m58q wrote

Those are exceptions rather than the rule for rare disease. Ashkenazi Jews had a bottleneck effect; SSD is a gain of function, etc. They other thing they have in common is a relatively high allele frequency in the general population.

For interference where a heterozygote would be effected (and therefore selected again) most variants would be de novo; so a homozygous mutant would require simultaneous and identical de novo mutations to occur in the same individual.

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lituranga t1_ja9pb51 wrote

Yes fair, just meaning to clarify that the phrase exceedingly improbable is a bit inaccurate since there are a huge amount of examples of disorders that work this way in reality.

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