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1. Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy

Author

Paul, Maimuna S., primary, Duncan, Anna R., additional, Genetti, Casie A., additional, Pan, Hongling, additional, Jackson, Adam, additional, Grant, Patricia E., additional, Shi, Jiahai, additional, Pinelli, Michele, additional, Brunetti-Pierri, Nicola, additional, Garza-Flores, Alexandra, additional, Shahani, Dave, additional, Saneto, Russell P., additional, Zampino, Giuseppe, additional, Leoni, Chiara, additional, Agolini, Emanuele, additional, Novelli, Antonio, additional, Blümlein Tobias B. Haack, Ulrike, additional, Heinritz, Wolfram, additional, Matzker, Eva, additional, Alhaddad, Bader, additional, Jamra, Rami Abou, additional, Bartolomaeus, Tobias, additional, AlHamdan, Saber, additional, Carapito, Raphael, additional, Isidor, Bertrand, additional, Bahram, Seiamak, additional, Ritter, Alyssa, additional, Izumi, Kosuke, additional, Shakked, Ben Pode, additional, Barel, Ortal, additional, Ben Zeev, Bruria, additional, Begtrup, Amber, additional, Carere, Deanna Alexis, additional, Mullegama, Sureni V., additional, Palculict, Timothy Blake, additional, Calame, Daniel G., additional, Schwan, Katharina, additional, Aycinena, Alicia R.P., additional, Traberg, Rasa, additional, Douzgou, Sofia, additional, Pirt, Harrison, additional, Ismayilova, Naila, additional, Banka, Siddharth, additional, Chao, Hsiao-Tuan, additional, and Agrawal, Pankaj B., additional

Published
2023
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2. Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy

Author

Maimuna S. Paul, Anna R. Duncan, Casie A. Genetti, Hongling Pan, Adam Jackson, Patricia E. Grant, Jiahai Shi, Michele Pinelli, Nicola Brunetti-Pierri, Alexandra Garza-Flores, Dave Shahani, Russell P. Saneto, Giuseppe Zampino, Chiara Leoni, Emanuele Agolini, Antonio Novelli, Ulrike Blümlein, Tobias B. Haack, Wolfram Heinritz, Eva Matzker, Bader Alhaddad, Rami Abou Jamra, Tobias Bartolomaeus, Saber AlHamdan, Raphael Carapito, Bertrand Isidor, Seiamak Bahram, Alyssa Ritter, Kosuke Izumi, Ben Pode Shakked, Ortal Barel, Bruria Ben Zeev, Amber Begtrup, Deanna Alexis Carere, Sureni V. Mullegama, Timothy Blake Palculict, Daniel G. Calame, Katharina Schwan, Alicia R.P. Aycinena, Rasa Traberg, Sofia Douzgou, Harrison Pirt, Naila Ismayilova, Siddharth Banka, Hsiao-Tuan Chao, Pankaj B. Agrawal, Paul, Maimuna S, Duncan, Anna R, Genetti, Casie A, Pan, Hongling, Jackson, Adam, Grant, Patricia E, Shi, Jiahai, Pinelli, Michele, Brunetti-Pierri, Nicola, Garza-Flores, Alexandra, Shahani, Dave, Saneto, Russell P, Zampino, Giuseppe, Leoni, Chiara, Agolini, Emanuele, Novelli, Antonio, Blümlein, Ulrike, Haack, Tobias B, Heinritz, Wolfram, Matzker, Eva, Alhaddad, Bader, Abou Jamra, Rami, Bartolomaeus, Tobia, Alhamdan, Saber, Carapito, Raphael, Isidor, Bertrand, Bahram, Seiamak, Ritter, Alyssa, Izumi, Kosuke, Shakked, Ben Pode, Barel, Ortal, Ben Zeev, Bruria, Begtrup, Amber, Carere, Deanna Alexi, Mullegama, Sureni V, Palculict, Timothy Blake, Calame, Daniel G, Schwan, Katharina, Aycinena, Alicia R P, Traberg, Rasa, Douzgou, Sofia, Pirt, Harrison, Ismayilova, Naila, Banka, Siddharth, Chao, Hsiao-Tuan, and Agrawal, Pankaj B

Subjects
Genetics, epilepsy, Drosophila, DEAD-box protein, neurodevelopmental disorder, Genetics (clinical), Article, transcription factor
Abstract

Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms.

Published
2023

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