Now, Northwestern Medicine and Broad Institute researchers find an RNA as the brake to regulate how much or how little protein a gene makes. In this rare disorder, patients don’t have the deleted long noncoding RNA called CHASERR, or ‘CHD2 adjacent, suppressive regulatory RNA,’ and the ‘foot’ is taken off ‘the brake,’ CHD2 protein production accelerates out of control, according to a new Northwestern Medicine study.
Most RNAs make proteins, but not long non-coding RNAs — they don’t make proteins, but they are essential for controlling how genes act. Still leftover in the spam folder of the human genome (the ‘Wild West’, 99%) are the long non-coding RNAs, which are not well known.
This finding has treatment implications for patients with neurodevelopmental disorders such as epilepsy and autism, and also motivates efforts to study underappreciated non-coding regions of the human genome. It’s a lot like … taking the foot off the brake.
The study was directed at the CHD2 gene which is linked to autism and epilepsy. Carvill and others found in 2013 that the CHD2 gene makes too little protein in a subset of patients with epilepsy and autism.
But this new study looked at three patients whose CHD2 gene was making too much protein. The one thing across all three patients was a deletion of the long non-coding RNA CHASERR.
Future studies that try to manipulate CHASERR could succeed in controlling the amount of CHD2 protein produced and therefore more effective treatments for patients might be possible, Carvill said.
Previous studies in mice by Igor Ulitsky from the Weizmann Institute have shown a link between deletion of CHASERR and the amount of CHD2 protein made, but this is the first showing the link in people.
“We’ve identified a unique mechanism and it’s possible that more long non-coding RNAs are at play in other rare genetic disorders that still need to be found that could potentially help solve some of the many families awaiting a rare-disease diagnosis,” said Kiran Musunuru.
The wild west of the human genome is sequenced.
Today when somebody goes to get his or her genetic testing done to actually look for variants (or gene changes) that may be related to genetic disorder or disease, they first get gene panels, or exome sequencing which is only 1% of our human genome that actually codes for proteins.
Scientists can conduct genome testing if they don’t identify genetic disorders or diseases via exome testing. In fact, little is understood about the full-genome’s function currently, so deciphering the results can be difficult.
“All the information that we now possess concerning disease stems from a genetic variant in a gene, which is because that material either abolishes the function of the protein or changes the function in some manner, but it is all protein based, and that is primarily because we have been performing exome sequencing,” Carvill commented.
Ideally, Carvill and her team would like to treat patients with epilepsy and other seizure-related disorders with gene-targeting therapies to correct the root cause: the genetic change.
One way her team is thinking about using their knowledge of the human genome to design gene-targeting therapies is that although we identified CHASERR to be devoid of protein-coding capability, it does regulate gene expression at the chromatin level.
Reference:
Little-studied RNA might be key to regulating genetic disorders like epilepsy, autism. Northwestern Now
