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Excess Protein Production Linked to Neurodevelopmental Disorder

by Kaia

Excessive protein production from the CHD2 gene can severely impact brain development and function. Patients with this issue often face a rare and debilitating neurodevelopmental disorder, leaving them wheelchair-bound, nonverbal, and with significant intellectual delays.

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Researchers at Northwestern Medicine and the Broad Institute of MIT and Harvard have identified an RNA that helps regulate protein production. This long non-coding RNA, known as CHASERR (CHD2 adjacent, suppressive regulatory RNA), is often deleted in patients with the disorder, leading to uncontrolled CHD2 protein production. This discovery will be published on October 23 in the New England Journal of Medicine.

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Unlike typical RNAs that code for proteins, long non-coding RNAs play a crucial role in gene regulation. They are found in the largely unexplored 99% of the human genome.

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This research has potential treatment implications for neurodevelopmental disorders like epilepsy and autism. It emphasizes the importance of studying these less-explored non-coding regions.

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“There are thousands of long non-coding RNAs, but until now, we didn’t understand their functions,” said Gemma Carvill, the study’s lead author.

Focus on CHD2 Gene

The study concentrated on the CHD2 gene, previously linked to autism and epilepsy. In 2013, Carvill’s team discovered that some patients produced too little protein from this gene. This new research, however, involved three patients whose CHD2 gene produced excessive protein due to the deletion of CHASERR.

Carvill suggests that future studies targeting CHASERR could help regulate CHD2 protein levels, potentially leading to better treatments.

While earlier research in mice indicated a connection between CHASERR deletion and protein production, this study is the first to confirm this link in humans. Igor Ulitsky, a long non-coding RNA expert from the Weizmann Institute, co-authored the paper.

Identifying a New Disorder

With only three patients, the researchers could classify this as a new disorder. “The unique mechanism we’ve found suggests there are more long non-coding RNAs linked to rare genetic disorders yet to be discovered,” said co-senior author Anne O’Donnell-Luria, a clinical genetics physician and professor at Harvard Medical School.

Emma’s Impact

Emma Broadbent, an 8-year-old patient, was the first identified in this study. She is wheelchair-bound, nonverbal, and uses a feeding tube. Her father, Brian, learned of her CHASERR deletion through genetic testing. He connected with Carvill and other researchers, leading to the identification of two more patients with the same deletion.

“Emma suffers a lot, and this adds purpose to her life because she’s helping science,” Brian said. “We feel responsible to advance this research for future children. This is just the beginning of something significant.”

Exploring the Human Genome

Currently, genetic testing typically focuses on the 1% of the genome that codes for proteins. “It’s astonishing that we only understand 1% of the human genome while knowing little about the other 99%,” Carvill noted. “Our study shows why we shouldn’t ignore it.”

If genetic disorders aren’t identified through standard tests, genome sequencing may be performed, but interpreting these results can be challenging due to the limited understanding of the genome’s functions.

“Most of our knowledge about diseases stems from genetic variants in protein-coding genes,” Carvill explained. “However, many cases remain unexplained, particularly in pediatric epilepsy.”

Future Treatment Possibilities

Currently, patients with epilepsy are often treated with antiseizure medications, which address symptoms but not the underlying cause. About 30% of epilepsy patients do not respond to existing treatments. Carvill’s team aims to develop gene-targeting therapies that address the root genetic changes. Discovering non-coding regions like CHASERR is a crucial step toward creating these therapies.

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