Rare mutations in 4 young men with severe COVID-19: Jamanet

This article in JAMANET released July 24 caught my eye because it ties in with something we’ve seen in this pandemic: men are more severely affected than women, and young people are less affected.

The article is a “case series”, an examination of 4 patients, young men with an average age of 26, who got severe COVID-19 and were on ventilators for an average of ten days; one died. Here’s what they found:

 Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]).

What does this mean? These men had two different mutations in the gene for the TLR7 (toll-like receptor 7) protein, which controls an important part of the immune system– one that is rarely needed. They had been perfectly healthy for an average of 26 years, until they came down with COVID-19.

This could have some implications for resistance to SARS-COV-2 infections: first, TLR7 seems to be vital for an innate resistance pathway to the virus. There could be other mutations that weaken this gene, which is on the X chromosome– meaning that men are more likely to be affected.

Since men only have one X chromosome, any defective gene on that chromosome will be automatically expressed throughout their bodies. Women who have a defect on one X chromosome could be less affected because that one is only expressed in half their body’s (bodies’?) cells.

In women, one of the two X chromosomes is inactivated in each cell early in development, apparently randomly. This creates a “chimera” (an organism that has a mixture of cells and DNA of two different individuals, like tortoiseshell cats) although not the kind of chimera you usually think of. This is only significant if one X has different genes from the other, say with mutations, that cause problems.

This may partially explain why men are over-represented among victims of severe COVID-19.

The second significance is that TLR7 is important, so boosting this pathway may lead to some form of treatment. People with deficiencies could receive something that makes up for it…

Finally, the TLR7 pathway may weaken with age, partially explaining why older people get sicker.

Look for more developments in this area in the (hopefully near) future.

One more point: I first read about this in “Scienmag”– and then lost it. It was on my iPhone news feed, along with a lot of other content from the same people. I didn’t pay much attention to the source until I looked up the reference on Google and got this hit (along with the journal paper I wanted, described above):

“Why I unfollowed Scienmag” from July 26, 2017, and lo and behold, it’s a wordpress blog!

It says that they got tired of looking at its articles (and twitters) because they never linked to their original source– the scientific paper they were based on. The reason? Greed for eyeballs. Unless you go to a sponsored link they lose you, and scientific journals don’t sponsor/be sponsored by scienmag.

Finally, the very name is an attempt to feed off of “Science” magazine, an already trusted source, which posted this article way back in 2015:

“Who’s in your tribe?” which is about being very selective about who and what you follow…