Examples of human genetic variations causing tissue-specific gene knock-out/knock-in

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Great question! In fact, I've been recently in search of examples of human genetic variations that cause tissue-specific knock-out and knock-in. Few examples that I know now 🧵 twitter.com/SherifMorris/status/1619730369334624258?s=20&t=RBQDeFapsMSAHFVnNoAcMA

1. A Greenland specific nonsense variant (p.Arg684Ter) knocks out the gene TBC1D4 only in the skeletal muscle (the variant causes late termination and so affects only the long isoform that is expressed only in skeletal muscle) nature.com/articles/nature13425

TBC1D4 regulates insulin mediated GLUT4 translocation to cell surface. GLUT4 is essential for glucose uptake into muscle and adipose tissue, especially after a rich carbohydrate meal.

As this variant knocks out TBC1D4 only in skeletal muscles, it increases risk of diabetes only in homozygous state by increasing postprandial blood glucose levels. This variant is a natural experiment to demonstrate the importance of skeletal muscle in glucose regulation.

And it turns out, even the homozygotes can regulate their postprandial blood glucose levels to the same level as wild types just with moderate daily exercise. So, this variant also demonstrates the importance of physical exercise in preventing diabetes. cbmr.ku.dk/news/2020/arctic-inuit-with-a-faulty-gene-could-control-their-diabetes-with-an-hour-of-daily-exercise/

2. Noncoding mutations in intron 2 of HK1 results in expression of hexokinase in pancreatic beta cells and cause congenital hyperinsulinism. HK1 is normally not expressed in beta cells and liver. nature.com/articles/s41588-022-01204-x

These noncoding rare mutations are natural experiments demonstrating the consequence of knocking in HK1 in a human tissue where it is normally not expressed. More in this thread. twitter.com/doctorveera/status/1473879664422637568?s=20&t=RBQDeFapsMSAHFVnNoAcMA

3. A non coding structural mutation results in expression of ASIP throughout the body, including brain hypothalamus, and causes morbid obesity. ASIP is normally expressed mainly in skin. nature.com/articles/s42255-022-00703-9

This variant is a natural experiment demonstrating the consequence of knocking in ASIP in hypothalamic neurons where it is normally not expressed. This example is special as here there is an extraordinary agreement between mice and human physiology. twitter.com/doctorveera/status/1605773329532456960?s=20&t=RBQDeFapsMSAHFVnNoAcMA

I guess there are many more examples like this either already discovered or yet to be discovered (they surely exist, given the human population size and number of generations humans have passed through already) twitter.com/doctorveera/status/1444449430867005441?s=20&t=RBQDeFapsMSAHFVnNoAcMA

Having said that, I agree that animal models are indispensable for drug target discoveries and certain complex experiments are easy and perhaps possible to perform only in animal models.

But there will be more success if we combine human genetics with animal models, rather than trusting only animal models. nature.com/articles/ng.3314