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The inactivation or deletion of the gene CHD2 and its product is associated with pediatric neurodevelopment disorders and pediatric epilepsy. But too much CHD2 can also cause problems—and the balance hinges on noncoding RNA.
A team of researchers from Northwestern University, Baylor University, and the Broad Institute of MIT and Harvard found that three unrelated children displaying a severe, unnamed neurodevelopmental disorder all had a deletion of a gene called CHASERR that codes for a long, noncoding RNA (N. Engl. J. Med, 2024, DOI: 10.1056/NEJMoa2400718). The CHASERR gene sits adjacent to the CHD2 gene, but it does not get translated into a protein, unlike its neighbor. The researchers found that the CHASERR deletion is associated with increased levels of CHD2 expression, which they linked to the children’s syndrome, including cognitive delays, differences in facial shape, and a lack of myelination in the nervous system. The effects of this deletion suggest that CHASERR regulates CDH2 expression.
The researchers found this association by taking small skin samples from two of the three children and using those cells to establish lines of induced pluripotent stem cells, which they could then use to analyze the levels of CHD2 protein.
“When we do genetic testing on individuals with a variety of human conditions, what we’re really doing is just looking at the protein-coding regions for the 1% of the genome that codes for proteins,” says Gemma Carvill of Northwestern University, one of the study’s senior authors. “We also need to be looking in the noncoding space, because genetic variants in the noncoding space can also impact the expression from other genes and therefore cause disease.”
Carvill says her laboratory is studying how CHASERR regulates CHD2. Jenny Hsieh, a neuroscientist at the University of Texas at San Antonio who was not involved with this research, says that these results should affect how disorders that stem from the lack of CHD2 protein should be treated. Treatment options, like antisense oligonucleotides that could lower the amount of CHASERR, need to avoid raising CHD2 levels too high.
“I think this gave us a clue that having too much of a protein can make things worse. We weren’t aware of that possibility,” she says.
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