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

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.

SUBMITTER: Paul MS

PROVIDER: S-EPMC9892767 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Paul Maimuna S MS Duncan Anna R AR Genetti Casie A CA Pan Hongling H Jackson Adam A Grant Patricia E PE Shi Jiahai J Pinelli Michele M Brunetti-Pierri Nicola N Garza-Flores Alexandra A Shahani Dave D Saneto Russell P RP Zampino Giuseppe G Leoni Chiara C Agolini Emanuele E Novelli Antonio A Blümlein Ulrike U Haack Tobias B TB Heinritz Wolfram W Matzker Eva E Alhaddad Bader B Abou Jamra Rami R Bartolomaeus Tobias T AlHamdan Saber S Carapito Raphael R Isidor Bertrand B Bahram Seiamak S Ritter Alyssa A Izumi Kosuke K Shakked Ben Pode BP Barel Ortal O Ben Zeev Bruria B Begtrup Amber A Carere Deanna Alexis DA Mullegama Sureni V SV Palculict Timothy Blake TB Calame Daniel G DG Schwan Katharina K Aycinena Alicia R P ARP Traberg Rasa R Douzgou Sofia S Pirt Harrison H Ismayilova Naila N Banka Siddharth S Chao Hsiao-Tuan HT Agrawal Pankaj B PB

American journal of human genetics 20221216 1

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 i ...[more]

PMID: 36528028

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Project description:We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Clinical and genetic data from affected individuals with neurological disorders were matched across families from five global sites. Here, we report five recessive CSPG4 (NM_001897) missense variants [three homozygous: c.A1370G (p.Asp457Gly), c.2627G>A (p.Arg876His) and c.3247C>A (p.Gln1083Lys), and two compound heterozygote: c.A1370G and c.5156A>G (p.Asp457Gly and p.Gln1719Arg) and c.658A>G and c.1220_1221delinsTG (p.(Thr220Ala and p.Pro407Leu)] by next-generation sequencing of five unrelated families with seven affected subjects. All subjects share a novel neurodevelopmental syndrome characterized by severe intellectual disability, global developmental delay, delayed ability to walk, speech and language delay, distinctive facial features, along with varying degrees of neurological impairment, including hypotonia, cerebellar hypoplasia, and/or seizures. All CSPG4 variants were predicted to be damaging using in silico tools, and three-dimensional molecular modeling suggested significant alterations in protein stability, compromising inter- and intra-molecular interactions. The impact on neurological and craniofacial development was analyzed in CRISPR/Cas9-mediated zebrafish models. CSPG4 variants affected notochord development, neuronal function, and cerebellar structure along with a disorganized head scaffold with anomalous skeletal and cartilage components. Two individuals metabolomics and crispant transcriptomics revealed significant perturbation of metabolites, extracellular matrix (ECM) regulating pathways, and genes previously described to cause mental retardation, dwarfism, and facial anomalies in humans. Our study links novel, rare, damaging variants of the ECM gene CSPG4 to a novel recessive Mendelian neurodevelopmental disorder in humans and supports the role of CSPG4 in early development.

Dataset Information

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

Publications

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

Similar Datasets

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