EIF4A2 Gene Linked to Rare Neurodevelopmental Disorder

A new study has identified a genetic cause for a rare neurodevelopmental disorder (NDD) known as developmental epileptic encephalopathy (DEE). The research, conducted by scientists at the Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, marks the first time that alterations in the Eukaryotic Initiation Factor 4A2 (EIF4A2) gene have been linked to human disease.

NDDs, which include conditions such as autism and epilepsy, affect 1-3% of the global population. DEEs are characterized by epilepsy and delayed development or loss of developmental skills, and it is estimated that single-gene epilepsies occur in around 1 in 2100 births annually. 

The EIF4A2 gene encodes an ATP-dependent RNA helicase, a protein that is involved in regulating the structure of ribonucleic acid (RNA). Previous research has linked the dysfunction of EIF4A2 to intellectual disability.

The study, published in the American Journal of Human Genetics, involved an international collaboration made possible by the MatchMaker Exchange, a virtual platform that allows clinicians and researchers to exchange data to accelerate genomic discovery. Their work began by identifying 15 individuals from 14 families with a mutated EIF4A2 gene, either by inheritance or spontaneous variations in one or both copies of EIF4A2. Molecular modeling suggests that these variations disrupt structural interactions in key protein domains.

In order to determine the pathogenicity of these variations in vivo, the researchers examined their effects on fruit flies and confirmed that they caused behavioral and developmental defects. They also found that complete loss of the EIF4A2 equivalent in fruit flies was lethal during embryonic stages, while reducing its levels in specific tissues was lethal during either embryonic or pupal stages.

When they overexpressed the wild-type human EIF4A2 in the eyes of fruit flies lacking the gene, they could fully "rescue" the pupal lethality and restore the average lifespan of the flies. Ultimately, the team concluded that EIF4A2 variations caused a genetic neurodevelopmental syndrome with mechanisms of both loss of function and gain of function.

"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 impairments," notes corresponding author Dr. Hsiao-Tuan Chao. "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 novel developmental epilepsy syndrome."

This new discovery provides an important step toward understanding the genetic basis of DEEs and could lead to the development of targeted therapies for these conditions. Further research is needed to determine the prevalence of DEEs and the full extent of the EIF4A2 gene's role in NDDs.