Alternative titles; symbols
HGNC Approved Gene Symbol: EIF4A2
Cytogenetic location: 3q27.3 Genomic coordinates (GRCh38): 3:186,783,577-186,789,897 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q27.3 | Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures | 620455 | Autosomal dominant; Autosomal recessive | 3 |
Eukaryotic initiation factor 4A plays an important role in the binding of mRNA to the 43S preinitiation complex when protein synthesis begins. Two highly homologous forms of functional EIF4A genes, Eif4a1 (602641) and Eif4a2, have been isolated in mice (Nielsen and Trachsel, 1988); yeast cells also possess 2 EIF4A genes, TIF1 and TIF2 (601993). The murine Eif4a and yeast TIF genes appear to belong to a DEAD-box gene family, whose members exhibit extensive amino acid similarity and contain the asp-glu-ala-asp (DEAD) sequence. DEAD-box genes have been identified in species ranging from E-coli to humans. Their function appears to be related to transcriptional/translational regulation.
Sudo et al. (1995) isolated human cDNA highly homologous to murine Eif4a2, which encodes one of the protein-synthesis initiation factors involved in the binding of mRNA to the ribosome. The human homolog was expressed in all normal tissues examined, but in variable amounts, being highly expressed in skeletal muscle and ovary, and less abundantly in liver, kidney, and pancreas.
Meijer et al. (2013) demonstrated that translational inhibition is the primary event required for mRNA degradation. Translational inhibition depends on miRNAs impairing the function of the eIF4F initiation complex. Meijer et al. (2013) defined the RNA helicase eIF4A2 as the key factor of eIF4F through which microRNAs function. They uncovered a correlation between the presence of miRNA target sites in the 3-prime untranslated region (UTR) of mRNAs and secondary structure in the 5-prime UTR, and showed that mRNAs with unstructured 5-prime UTRs are refractory to miRNA repression. Meijer et al. (2013) concluded that their data supported a linear model for miRNA-mediated gene regulation in which translational repression via eIF4A2 is required first, followed by mRNA destabilization.
Nielsen et al. (1993) mapped the mouse Eif4a2 gene to chromosome 16. By fluorescence in situ hybridization, Sudo et al. (1995) mapped the EIF4A2 gene to 18p11.2. The International Radiation Hybrid Mapping Consortium mapped the EIF4A2 gene to chromosome 3 (WI-30529) in a region of conserved synteny with mouse chromosome 16.
In 10 unrelated patients (P6-P15) with neurodevelopmental disorder with hypotonia and speech delay, with or without seizures (NEDHSS; 620455), Paul et al. (2023) identified de novo heterozygous missense mutations in the EIF4A2 gene (601102.0001-601102.0004). The patients were ascertained through collaborative efforts, including Matchmaker Exchange, after exome sequencing identified the mutations. All mutations occurred in 1 of 2 main functional domains, the C-terminal helicase domain or the N-terminal helicase ATP-binding domain, and were predicted to hinder protein function. None of the mutations were present in the gnomAD database. Studies of patient cells were not performed. Various functional expression studies of 4 of the missense mutations in Drosophila showed that 3 mutations (G364E, L344F, and T243I), all located within or adjacent to the helicase C-terminal domain, resulted in climbing defects and disturbed eye development, and were unable to fully rescue lethality in eif4a2-null flies, consistent with a dominant loss-of-function effect. The fourth mutation (T216I), located in the N- terminal helicase ATP-binding domain, did not affect climbing, but caused defective wing development and was completely unable to rescue lethality, consistent with a toxic gain-of-function effect. These 10 patients had a severe phenotype. In addition, 2 sibs (P4 and P5) with a severe phenotype were found to be compound heterozygous for a frameshift and an in-frame deletion (601102.0005 and 601102.0006). Of note, 3 additional patients (P1, P2, and P3) with a mild phenotype were also identified: however, P1 carried a de novo heterozygous S2C variant that was present in 1 of 251,478 alleles in gnomAD (frequency of 4.0 x 10(-6)) and P3 was mosaic for a frameshift variant. P2, born of consanguineous Syrian parents, was homozygous for an in-frame deletion (D37del) that was also found once in the heterozygous state in gnomAD. All 3 of these variants occurred in the N terminus upstream of the functional domains; studies of these variants were not performed. Paul et al. (2023) suggested that phenotypic variability in patients with mono- or biallelic EIF4A2 variants likely depends on the degree of functional impairment of the mutant protein.
The Drosophila Eif4a2 gene encodes a negative regulator of decapentaplegic (Dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity formation. Complete loss of Eif4a2 in the fly results in pupal lethality (Paul et al., 2023).
In a 5-year-old boy (P15) with neurodevelopmental disorder with hypotonia and speech delay, with seizures (NEDHSS; 620455), Paul et al. (2023) identified a de novo heterozygous c.1091G-A transition (c.1091G-A, NM_001967.3) in the EIF4A2 gene, resulting in a gly364-to-glu (G364E) substitution at a conserved residue in the helicase C-terminal domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the parents or in the gnomAD database. Expression of the mutation in wildtype Drosophila resulted in defects in climbing ability. In addition, the mutation was unable to fully rescue lethality in eif4a2-null flies. These findings were consistent with a dominant loss-of-function effect.
In a 9-year-old Lithuanian boy (P13) with neurodevelopmental disorder with hypotonia and speech delay, with seizures (NEDHSS; 620455), Paul et al. (2023) identified a de novo heterozygous c.1032G-C transversion (c.1032G-C, NM_001967.3) in the EIF4A2 gene, resulting in a leu344-to-phe (L344F) substitution at a conserved residue in the helicase C-terminal domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the parents or in the gnomAD database. Expression of the mutation in wildtype Drosophila resulted in defects in climbing ability and abnormal eye development associated with toxic upregulation of Dpp signaling. In addition, the mutation was unable to fully rescue lethality in eif4a2-null flies. These findings were consistent with a dominant loss-of-function effect.
In a 9.5-year-old girl (P11) with neurodevelopmental disorder with hypotonia and speech delay, with seizures (NEDHSS; 620455), Paul et al. (2023) identified a de novo heterozygous c.728C-T transition (c.728C-T, NM_001967.3) in the EIF4A2 gene, resulting in a thr243-to-ile (T243I) substitution at a conserved residue adjacent to the helicase C-terminal domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the parents or in the gnomAD database. Expression of the mutation in wildtype Drosophila resulted in defects in climbing ability and abnormal eye development. The mutation was unable to fully rescue lethality in eif4a2-null flies. These findings were consistent with a dominant loss-of-function effect.
In a 48-month-old boy (P10) with neurodevelopmental disorder with hypotonia and speech delay, with seizures (NEDHSS; 620455), Paul et al. (2023) identified a de novo heterozygous c.647C-T transition (c.647C-T, NM_001967.3) in the EIF4A2 gene, resulting in a thr216-to-ile (T216I) substitution at a conserved residue in the N-terminal helicase ATP-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the parents or in the gnomAD database. Neuronal expression of the mutation in Drosophila did not result in defects in climbing ability, but expression of the mutation in larval wing structures caused wing margin serrations. This abnormality was associated with reduced Dpp signaling. In addition, the mutation completely failed to rescue pupal lethality in eif4a2-null flies. The findings were consistent with a toxic gain-of-function effect.
In 2 sibs (P4 and P5) with neurodevelopmental disorder with hypotonia and speech delay, with seizures (NEDHSS; 620455), Paul et al. (2023), identified compound heterozygous mutations in the EIF4A2 gene: a 2-bp deletion (c.186_187del, NM_001967.3), predicted to result in a frameshift and premature termination (Arg62SerfsTer7), and a 6-bp in-frame deletion (c.1161_1166del; 601102.0006), predicted to result in the deletion of 2 residues (Asp387_Ile388del) in the C-terminal helicase domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Neither mutation was present in the gnomAD database. Functional studies of the variants were not performed.
For discussion of the 6-bp in-frame deletion (c.1161_1166del, NM_001967.3) in the EIF4A2 gene, predicted to result in the deletion of 2 residues (Asp387_Ile388del), that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with hypotonia and speech delay, with seizures (NEDHSS; 620455) by Paul et al. (2023), see 601102.0005.
Meijer, H. A., Kong, Y. W., Lu, W. T., Wilczynska, A., Spriggs, R. V., Robinson, S. W., Godfrey, J. D., Willis, A. E., Bushell, M. Translational repression and eIF4A2 activity are critical for microRNA-mediated gene regulation. Science 340: 82-85, 2013. [PubMed: 23559250] [Full Text: https://doi.org/10.1126/science.1231197]
Nielsen, P. J., Rochelle, J. M., Seldin, M. F. The functional genes for protein synthesis initiation factor 4AI and 4AII map to mouse chromosomes 11 and 16. Mammalian Genome 4: 185-186, 1993. [PubMed: 8439732] [Full Text: https://doi.org/10.1007/BF00352237]
Nielsen, P. J., Trachsel, H. The mouse protein synthesis initiation factor 4A gene family includes two related functional genes which are differentially expressed. EMBO J. 7: 2097-2105, 1988. [PubMed: 3046931] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03049.x]
Paul, M. S., Duncan, A. R., Genetti, C. A., Pan, H., Jackson, A., Grant, P. E., Shi, J., Pinelli, M., Brunetti-Pierri, N., Garza-Flores, A., Shahani, D., Saneto, R. P., and 35 others. Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy. Am. J. Hum. Genet. 110: 120-145, 2023. Note: Erratum: Am. J. Hum. Genet. 110: 548 only, 2023. [PubMed: 36528028] [Full Text: https://doi.org/10.1016/j.ajhg.2022.11.011]
Sudo, K., Takahashi, E., Nakamura, Y. Isolation and mapping of the human EIF4A2 gene homologous to the murine protein synthesis initiation factor 4A-II gene Eif4a2. Cytogenet. Cell Genet. 71: 385-388, 1995. [PubMed: 8521730] [Full Text: https://doi.org/10.1159/000134145]