AbouBenAdhem t1_ja95g5v wrote
Reply to comment by jubears09 in Is there a genetic disease where the heterozygote has more severe disease symptoms than the homozygote? by Altranite-
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?
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.
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.
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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