Discovered a new neurodevelopmental epilepsy and its genetic cause

Neurodevelopmental disorders (NDDs) encompass highly prevalent conditions such as autism and epilepsy, with cognitive disabilities alone affecting 1-3% of the world’s population. Developmental epileptic encephalopathies (DEEs) are NDDs characterized by epilepsy and developmental delay or loss of developmental skills. Although the prevalence of DEE has yet to be determined, studies estimate that single-gene epilepsies occur in about 1 in 2,100 births per year. A recent study from the laboratories of Dr. Hsiao-Tuan Chao, an assistant professor at Baylor College of Medicine (BCM) and an investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, and Dr. Pankaj Agrawal, a professor at Harvard Medical School and Children’s Hospital Boston, identified alterations in the Eukaryotic Initiation Factor 4A2 (EIF4A2) gene as the cause of a new DEE syndrome.

this new discoverypublished in the american journal of human geneticsprovides the first experimental demonstration of a causal role for alterations affecting EIF4A2 in human disease.

Identification of persons with a new neurodevelopmental disorder

The study involved a international collaboration That was made possible by a virtual tool called MatchMaker Exchange, which was launched in 2013 to serve as an integrated platform for clinicians and researchers from 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-senior author of the study, identified about 15 people from 14 families who had structural brain changes (seen by MRI) and similar clinical symptoms. . presentations including global developmental delays, poor muscle tone, speech problems and epilepsy,” Chao said. “They found that these individuals carried extremely rare spontaneous mutations in one or both copies of EIF4A2.”

The EIF4A2 gene encodes an ATP-dependent RNA helicase, a protein It is involved in the regulation of the three-dimensional (3D) structure of a fundamental molecule, ribonucleic acid (RNA). The EIF4A2 protein is expressed in all tissues and acts 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, a fundamental molecular process by which messenger RNAs are converted into their corresponding proteins. Previous studies have implicated EIF4A2 as critical in brain development and its dysfunction has been associated with intellectual disability.

Using fruit flies to understand how mutations in elF4A cause this syndrome

To confirm whether these genetic variants are responsible for the neurological symptoms seen in these patients, co-senior author Dr. Maimuna Sali Paul, a postdoctoral fellow in Chao’s lab, and Dr. Chao carefully examined human variants of EIF4A2 and its fruit fly counterpart, elF4A, with the that share significant sequence similarity.

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

in a variety of behavioral and developmental defects, such as motor defects, and improper development of the eyes, wings, and peripheral nervous system organs, such as bristles, a clear indication of their toxicity.

In addition, Dr. Paul took advantage of the knowledge that complete loss of eIF4A was lethal in the embryonic stages of the fruit fly, while reduction of its levels in specific tissues was lethal in the embryonic or pupal stages, to study the functional consequences of human variants of EIF4A2. “More 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 to these flies,” said Dr. Dr Paul. “However, overexpression of one disease-causing variant resulted in weak/partial rescue, while the others failed to rescue lethality, a clear indication of the essential role they play during development.”

“In line with this study, our lab had previously found that loss of a kinase, EIF2AK2, which regulates downstream protein complexes involved in protein translation, also causes similar neurological deficits,” Dr. Chao said. “Thus, our findings in this study underscore the critical role of balanced regulation of protein translation for brain development and maintenance of function in neurons and glia. These findings reveal that EIF4A2 is a previously unknown cause.” recognition of a new syndrome of developmental epilepsy”.

Provided by Texas Children’s Hospital