Discovery of a new neurodevelopmental seizure disorder and its genetic cause

Discovery of a new neurodevelopmental seizure disorder and its genetic cause


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Neurodevelopmental disorders (NDD) encompass such widespread conditions as autism and epilepsy, with cognitive disorders alone affecting 1-3% of the world’s population. Developmental epileptic encephalopathies (DEE) are DNDs characterized by epilepsy and developmental delay or loss of developmental abilities. Although the prevalence of EEDs remains to be determined, studies estimate that monogenic epilepsies occur in approximately 1 in 2100 births per year. A recent study from the labs of Dr. Hsiao-Tuan Chao, assistant professor at Baylor College of Medicine (BCM) and researcher at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, and Dr. Pankaj Agrawal, professor at the Harvard Medical School and Boston Children’s Hospital has identified alterations in the eukaryotic initiation factor 4A2 (EIF4A2) gene as the cause of a novel DEE syndrome.

This new discovery, published in the American Journal of Human Geneticsprovides the first experimental demonstration of a causal role of alterations impacting EIF4A2 in human disease.

Identify people with a new neurodevelopmental disorder

The study involved international collaboration made possible by a virtual tool called MatchMaker Exchange, which was launched in 2013 to serve as an integrated platform for clinicians and researchers around the world to exchange phenotypic and genotypic data, which dramatically accelerates genomic discovery.

“Using this tool, Dr. Anna Duncan, a teacher in Dr. Agrawal’s lab and co-first author of the study, identified about 15 people from 14 families who had structural changes in the brain (such as observed by MRI imaging) and similar clinical symptoms. presentations including global developmental delays, low muscle tone, speech impairment 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 involved in regulating 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 elF4A mutations cause this syndrome

To confirm whether these genetic variants are responsible for the neurological symptoms seen in these patients, co-first author Dr. Maimuna Sali Paul, a postdoctoral fellow at the Chao lab, and Dr. Chao carefully examined the human variants EIF4A2 and its counterpart from the fruit fly. , elF4A, with which it shares significant sequence similarity.

They identified four EIF4A2 variants that affected conserved residues in the fly eIF4A gene and which, according to molecular modeling data, disrupted 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 eyes, wings and peripheral nervous system organs such as body hair, a clear indication of their toxicity.

Additionally, Dr. Paul leveraged knowledge that complete loss of eIF4A was lethal in fruit fly embryonic stages, while reduction of its levels from specific tissues was lethal in embryonic or pupal stages. , to study the functional consequences of human variants of EIF4A2. “Most importantly, when we overexpressed wild-type human EIF4A in the eyes of flies lacking this gene, we were able to completely ‘rescue’ pupae lethality and restore the normal lifespan of these flies,” said said Dr. Paul. “However, overexpression of one pathogenic variant resulted in weak/partial rescue while the others failed to rescue lethality – a clear indication of the critical role they play during development.”

“Consistent 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 disorders,” 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 EIF4A2 as a previously unrecognized cause of ‘a new developmental epilepsy syndrome.’

More information:
Maimuna S. Paul et al, rare variants of EIF4A2 are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia and epilepsy, The American Journal of Human Genetics (2022). DOI: 10.1016/j.ajhg.2022.11.011

Provided by Texas Children’s Hospital

Quote: Discovery of a new neurodevelopmental epilepsy disorder and its genetic cause (December 16, 2022) Retrieved December 16, 2022 from

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