Here is a genetic disease, where we’ve known exactly what’s wrong with the causative gene for 23 years, over 10,000 papers have been written (a Google search comes up with about 418,000 results (0.45 seconds), but we don’t know how the mutation causes the problems it does or have a clue how to treat the disease. So much for finding the cause of a genetic disease leading to therapy. Imagine how much harder cancer is.
I speak of Huntington’s chorea, and the causative gene huntingtin. It’s a terrible neurologic disease characterized by progressive movement disorders, dementia and incapacitation over a decade or two. Woodie Guthrie had it; fortunately Arlo escaped. Like many people with the disorder Woodie was quite fertile, having 8 children.
It being a neurologic disorder, I’ve read a lot about it, and my jottings about my readings over the past few decades have consumed 83,635 characters (aren’t computers wonderful)? I’ve had a fair amount of experience with it, as an Indian agent in Montana had it, and produced many progeny with his women, leading to a good deal of devastation in one tribe.
Neuron vol. 89 pp. 910 – 926 ’16 is an excellent recent review (but not one for the fainthearted). Several mysteries are immediately apparent.
First huntingtin is expressed in nearly every neuron, but only a few die. It is expressed outside the brain in lung ovary and testes, but they work just fine.
Second Huntingtin interacts with over 350 different proteins. Figuring which are the important ones has provided steady employment.
Third it exists in many forms, so many that there aren’t enough scientists living to test them all. This is because huntingtin is subject to a variety of chemical modifications (phosphorylation, ubiquitination, acetylation, palmitoylation, sumoylation) at FORTY-EIGHT different sites (listed in the article). So this gives 2^48 possible modified forms of the protein (either modification being present or absent). 2^48 = 281,474,976,710,656 if you’re interested.
In addition to the modifications, the protein is huge — some 3,144 amino acids occurring in 67 exons forming two mRNAs of 10,366 and 13.711 nucleotides.
Fourth The protein can also be chopped up by at least 5 different enzymes at 6 different sites, and some fragments are biologically active (toxic in tissue culture).
Naturally, the region with the mutation (near the amino terminal end) of the protein has been studied most intensively.
Huntingtin has its fingers in many physiologic pies — the reference is excellent in this area — these include vesicular trafficking, cell division, cilia formation, endocytosis, autophagy, gene transcription. Abnormalities of which one causes the neurologic disease.
The mutant form forms protein aggregates. Like Alzheimer’s disease senile plaque or the Lewy body of Parkinson’s disease, we don’t know if the aggregates are toxic or protective.
Fifth: Despite all its known functions we don’t know if the mutation produces a loss of some vital function of Huntingtin, or a new and toxic function.
Even worse, compared to cancer, Huntington’s chorea is ‘simple’ because we know the cause.