A new neurodevelopmental epilepsy disorder and its genetic cause discovered

Neurodevelopmental disorders (NDDs) include very common conditions such as autism and epilepsy, and cognitive impairment alone affects 1-3% of the world’s population. Developmental epileptic encephalopathy (DEE) is an NDD characterized by epilepsy and developmental delay or loss of developmental abilities. Although the prevalence of DEE has not yet been determined, monogenic epilepsy is estimated to occur in approximately 1 in 2,100 live births per year. A recent study from the lab of Dr. Xiao Tuan Chao and Dr. Pankaji Agrawal, assistant professors at Baylor College of Medicine (BCM) and investigators at the Jiang and Duncan Duncan Neurological Institute (Duncan NRI) at Texas Children’s Hospital, A professor at Harvard Medical School and Boston Children’s Hospital has identified alterations in the eukaryotic initiation factor 4A2 (EIF4A2) gene as the cause of the new DEE syndrome.

this new discover, American Journal of Human Geneticsprovides the first experimental demonstration of a causative role for changes affecting EIF4A2 human disease.

Identification of individuals with new neurodevelopmental disorders

This study includes International cooperation This was made possible by a virtual tool called MatchMaker Exchange, launched in 2013. This tool serves as an integrated platform for clinicians and researchers around the world to exchange phenotypic and genotypic data, greatly accelerating genomic discovery.

“Using this tool, Dr. Anna Duncan, an instructor in Dr. Agrawal’s lab and co-first author of the study, identified about 15 people from 14 families and had structural changes (MRI) in their brains. “We saw clinical changes similar to those observed in the imaging presentation, including global developmental delay, decreased muscle tone, speech impairment, and epilepsy,” Chao said. We found that individuals carry very rare spontaneous mutations in one or both copies of EIF4A2.”

The EIF4A2 gene encodes an ATP-dependent RNA helicase. protein It is involved in regulating the three-dimensional (3D) structure of the basic molecule, ribonucleic acid (RNA). The EIF4A2 protein is expressed in all tissues and functions as a regulator of protein translation. It belongs to the DEAD-box family, a group of 50 closely related proteins, many of which regulate protein translation, the fundamental molecular process by which messenger RNA is converted into the corresponding protein.Previous studies suggest that EIF4A2 is important brain development and its dysfunction is associated with intellectual disability.

Using Drosophila to understand how mutations in elF4A cause this syndrome

To see if these gene variants are the cause neurological symptoms As seen in these patients, co-first authors Maimuna Sali Paul, Ph.D., a postdoctoral fellow in Chao’s lab, and Dr. Chao carefully examined the human EIF4A2 variant and its fruit fly counterpart, elF4A.

They identified four variants of EIF4A2 that affect conserved residues in the fly gene eIF4A and were predicted by molecular modeling data to disrupt the 3D structure of human EIF4A and its interaction with RNA. . Dr. Paul found that these EIF4A2 variants of his were overexpressed in Drosophila.

A clear indication of their toxicity is in various behavioral and developmental disorders, such as movement disorders, and in the inappropriate development of peripheral nervous system organs such as eyes, wings, and bristles.

Furthermore, Dr. Paul leveraged the knowledge that complete loss of eIF4A is lethal at the embryonic stage of Drosophila, whereas reduced levels from specific tissues are lethal at either the embryonic or pupal stage. We have studied the functional consequences of human EIF4A2 variants. “Most importantly, when we overexpressed wild-type human EIF4A in the eyes of flies lacking this gene, we were able to completely ‘rescue’ pupal lethality and restore normal lifespan in these flies. It’s done,” Dr. Paul said. “However, overexpression of one disease-causing variant resulted in weak/partial rescue, whereas the other variant failed to rescue lethality. clearly shows their role.”

“Consistent with this study, our lab has previously found that loss of EIF2AK2, a kinase that regulates downstream protein complexes involved in protein translation, also causes similar neurological deficits,” Chao said. said Dr. “Thus, our findings in this study highlight the critical role of the balanced regulation of protein translation for the maintenance of brain development and function in neurons and glia. These findings suggest that EIF4A2 We are revealing that it is the cause of a new developmental epilepsy syndrome that has not been recognized until now.”

Courtesy of Texas Children’s Hospital