David enjoys walking, but his balance and coordination are not good. He has taken many falls in his lifetime. Sometimes he hits his head. He has had numerous stitches over his eye, on his forehead and has injured his nose more than once. I have always worried that these falls might have a cumulative effect on his brain.
In 2019, just before COVID-19 started to spread, a group of researchers in Shandong, China asked the question: what does the gene CELSR1 do? CELSR1 is on my list of high importance genes of PMS (see Which PMS genes are most important?) One copy of CELSR1 is missing in about half of all people with Phelan-McDermid syndrome who have a terminal deletion of chromosome 22. Only a few months ago I wrote about the relationship between CELSR1 and lymphedema (see Have we found the gene that causes Lymphedema?), based on research done elsewhere in China. As I describe in that blog, research on CELSR1 has become truly international.
It has been known for years that the CELSR1 gene is especially active (producing the celsr1 protein) following a brain injury. The celsr1 protein is associated with the creation of new neurons and enhancing the blood flow in the brain. Until now, it was not clear if the increase in celsr1 protein following injury protects the brain. Now we know a lot more. I will describe the research (see the scientific paper here).
The researchers used a very modern technique. They used a “short hairpin RNA” (shRNA) to reduce protein production by the CELSR1 gene in rodents. This method cut the level of the celsr1 protein production by 50%. Humans missing one copy of the CELSR1 gene should also have about a 50% loss in protein production. In other words, this is an animal model of PMS!
Using a standardized procedure to invoke a brain bleed in rats, the researchers looked to see if rats lacking half of the normal celsr1 sustained more brain damage than expected. Both the amount of brain damage and the ability to walk were significantly affected by the reduced celsr1. The researchers then refined their methods to analyze exactly how celsr1 was protecting the brain. Celsr1 is an amazing protein. It protects injured neurons from dying, it speeds up the production of new neurons and it promotes the formation of new blood vessels to provide oxygen to the injured region. The researchers were also able to pinpoint what part of the brain jumps into action when the celsr1 is needed.
For years, scientists have been looking for natural substances that might protect the brain after a bleed. These “neuroprotective” substances have been studied and they include familiar chemicals, like IGF-1. Thus far, none of the known chemicals or their derivatives have provided useful treatments for brain injury, intellectual disability or autism. The question becomes, is celsr1 nature’s way of protecting the brain? Perhaps we should be focused on restoring the normal level in people missing the CELSR1 gene?
We know that, in general, people with PMS who have larger than average deletions (average size is about 4.5 Mb) have more deficits/problems than people with smaller deletions. This has been shown repeatedly. What we do not know is whether people with deletions greater that 4.5 Mb accumulate brain damage over time. The brain bleeds (strokes) in the rat study are severe enough that a few of the animals die from the bleed. But, are smaller events — perhaps events that David experienced — causing serious long term problems because of the missing CELSR1? If these problems accumulate, perhaps the deletion size will be more important in older people with PMS.
This new information about CELSR1 reminds us that with each important gene comes an opportunity to help people with PMS. Some of the important genes remain poorly characterized. As we are seeing with CELSR1, the more we study these less-well-known genes, the more opportunities we have to develop new treatments.
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arm22q13 