Heterozygous variants in the EEF1A2 gene are associated with a form of early infantile epileptic encephalopathy (EIEE33; OMIM 616409) and a form of autosomal dominant intellectual disability (MRD38; OMIM 616393), a less severe disorder with overlapping features. De Ligt et al., 2012 and Nakajima et al., 2014 identifed de novo missense variants in the EEF1A2 gene in three unrelated patients presenting with intellectual disability, epilepsy, and autistic features. Additional de novo missense variants in this gene were identified in patients presenting with intellectual disability and epilepsy in Lam et al., 2016. A novel de novo missense variant in this gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; however, this variant was reportedly predicted to be benign in Sanders et al., 2015.
Molecular Function
This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability, autistic behaviors and epilepsy.
Validation of targeted next-generation sequencing panels in a cohort of Polish patients with epilepsy: assessing variable performance across clinical endophenotypes and uncovering novel genetic varian
CRISPR/Cas9 generated eEF1A2 biallelic mutant mice exhibit motor neuron degeneration, severe neurodevelopmental disorder, sudden death and audiogenic seizures. The presence of the human mutant eEF1A2 carrying the mutation G70S did not rescue neurodegeneration in eEF1A2-G70S heterozygous mutant mice, indicating that the mutant protein is non-functional (Davies FC, et al., Sci Rep., 2017).
References
Type
Title
Author, Year
Primary
Biallelic mutations in the gene encoding eEF1A2 cause seizures and sudden death in F0 mice.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with biallelic deletions (/) in EEF1A2. Guide RNA pairs were designed on mouse Eef1a2 around exon 3. gRNAs, Cas9n mRNA and Ultramer ssODN (single stranded oligonucleotide) repair template were injected into single cell C57BL/6 embryos. Sequencing confirmed a deletion close to the PAM site (protospacer adjacent motif). All null alleles resulted in premature stop codons and nonsense-mediated decay (mice with two such alleles are categorised as /).
Allele Type: Loss of function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: C57BL/6
Model Source: 28378778
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with monoallelic deletions (+/) in EEF1A2. Guide RNA pairs were designed on mouse Eef1a2 around exon 3. gRNAs 25 ng/microliter each, Cas9n mRNA at 50 ng/microliter and Ultramer ssODN repair template 150 ng/microliter were injected into single cell C57BL/6 embryos. Sequencing confirmed a deletion close to the PAM site (protospacer adjacent motif). All null alleles resulted in premature stop codons and nonsense-mediated decay (mice with one such alleles are categorised as +/).
Allele Type: Loss of function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: C57BL/6
Model Source: 28378778
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with the G70S missense mutation in exon 3 were detected by the absence of the MnlI restriction site that was destroyed if the G70S mutation had been introduced. F0 founder mice were analyzed as no G70S/+ mice were obtained from which to establish breeding lines.
Allele Type: Loss of function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: C57BL/6
Model Source: 28378778
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with the biallelic G70S missense mutation in exon 3 were detected by the absence of the MnlI restriction site that was destroyed if the G70S mutation had been introduced. F0 founder mice were analyzed. There was no evidence of indels.
Allele Type: Loss of function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: C57BL/6
Model Source: 28378778
Model Type:
Genetic
Model Genotype:
Compound heterozygous
Mutation:
Mice with an EEF1A2 allele with a 21 bp in-frame deletion (del/).
Allele Type: Loss of function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: C57BL/6
Model Source: 28378778
Model Type:
Genetic
Model Genotype:
Compound heterozygous
Mutation:
Compound heterozygous mice with a deletion on one allele and the G70S-causing mutation on the other allele (G70S/). The G70S mutation was incorporated by homology directed repair (HDR) and non-homologous end joining (NHEJ) resulted in a deletion on the other allele.
Allele Type: Loss of function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: C57BL/6
Model Source: 28378778
Model Type:
Genetic
Model Genotype:
Other
Mutation:
Mice with complex mutations in the EEF1A2 alleles. Of some that could be genotyped, one had two insertions of 50bp and 250bp in exon 3, four had evidence of G70S incorporation on at least one allele but subsequent analysis showed that the missense mutations were in cis with deletions and therefore not expressed. Most indels found were 140 bp deletions located close to the 5 PAM site on the intron/exon boundary that had not been mutated in the repair template because of the possibility of introducing splicing artefacts. The mosaicism may arise from continued Cas9-induced mutagenesis after zygotic cleavage.
Allele Type: Loss of function
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Mutant ES Cell Line: C57BL/6
Model Source: 28378778
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Eef1a2^E122K allele was generated using CRISPR-Cas9 technology. Two 200-nucleotide single-stranded oligodeoxynucleotide (ssODN) repair templates were designed to target the genomic sequence of Eef1a2. The first repair template contained three single nucleotide substitutions resulting in E122K missense. E122K founder mice were generated by perinuclear microinjection of crRNAannealed totracrRNA and Cas9 nuclease ribonucleoprotein complexes along with ssODN repair templates into fertilized C57BL/6JCrl oocytes. Founder mice that carried E122K alleles, complete with silent protospacer-adjacent motif mutation and novel PstI site, and survived to breeding age, were mated with C57BL/6J stock.
Allele Type: ASD mutation
Strain of Origin: C57BL/6JCrl
Genetic Background: C57BL/6J
ES Cell Line: N/A
Mutant ES Cell Line: Model Source: Catherine M. Abbott (University of Edinburgh)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The Eef1a2^E122K allele was generated using CRISPR-Cas9 technology. Two 200-nucleotide single-stranded oligodeoxynucleotide (ssODN) repair templates were designed to target the genomic sequence of Eef1a2. The first repair template contained three single nucleotide substitutions resulting in E122K missense. E122K founder mice were generated by perinuclear microinjection of crRNAannealed totracrRNA and Cas9 nuclease ribonucleoprotein complexes along with ssODN repair templates into fertilized C57BL/6JCrl oocytes. Founder mice that carried E122K alleles, complete with silent protospacer-adjacent motif mutation and novel PstI site, and survived to breeding age, were mated with C57BL/6J stock.
Allele Type: ASD mutation
Strain of Origin: C57BL/6JCrl
Genetic Background: C57BL/6J
ES Cell Line: N/A
Mutant ES Cell Line: Model Source: Catherine M. Abbott (University of Edinburgh)
Description: Mutants show a neurodegenerative phenotype, particularly motor neuron degeneration, compared to controls. nuclear enlargement and cytoplasmic degeneration were noted in mutant spinal motor neurons.
Exp Paradigm: NA
Description: Mutants show increased frequency of fatal tonic clonic seizures preceded by the wild running, compared to controls.
Exp Paradigm: Audiogenic seizures were observed: seizures in response to transient environmental noise.
Description: Mutants show a sudden death phenotype compared to controls. mutants die latest by 28 days after birth. sudden deaths were a result of audiogenic seizures.
Exp Paradigm: NA
Description: Mutants show decreased expression of eef1a2 compared to controls. mutants show the absence of bands at 73 bp and 39 bp in mnli restriction digests of rt-pcr products suggesting that no wild-type allele is being expressed.
Exp Paradigm: Western blot
Description: Mutants show decreased expression of eef1a2 compared to controls. mutants show the absence of bands at 73 bp and 39 bp in mnli restriction digests of rt-pcr products suggesting that no wild-type allele is being expressed.
Exp Paradigm: Semi-quantitative pcr (qrt-pcr)
Description: Mutants show a neurodegenerative phenotype, particularly motor neuron degeneration, compared to controls. mutants exhibit a more severe phenotype than mice null for eef1a2.
Exp Paradigm: NA
Description: Mutants show no change in expression of eef1a2 compared to controls. mutants show the absence of bands at 73 bp and 39 bp in mnli restriction digests of rt-pcr products suggesting that no wild-type allele is being expressed.
Exp Paradigm: Western blot
Description: Mutants show no change in expression of eef1a2 compared to controls. mutants show the absence of bands at 73 bp and 39 bp in mnli restriction digests of rt-pcr products suggesting that no wild-type allele is being expressed.
Exp Paradigm: Semi-quantitative pcr (qrt-pcr)
Description: Mutants show increased frequency of seizures compared to controls.
Exp Paradigm: Audiogenic seizures were observed: seizures in response to transient environmental noise.
Description: Mutants show a neurodegenerative phenotype, particularly motor neuron degeneration, compared to controls. nuclear enlargement and cytoplasmic degeneration were noted in mutant spinal motor neurons.
Exp Paradigm: NA
Description: Mutants show a sudden death phenotype compared to controls. mutants exhibit a more severe wasted phenotype than mice null for eef1a2.
Exp Paradigm: NA
Description: Mutants show decreased body weight compared to controls. mutants are smaller compared to homozygous null mutants of eef1a2.
Exp Paradigm: NA
Description: Mutants show no change in expression of eef1a2 compared to controls. mutants show the absence of bands at 73 bp and 39 bp in mnli restriction digests of rt-pcr products suggesting that no wild-type allele is being expressed.
Exp Paradigm: Western blot
Description: Mutants show no change in expression of eef1a2 compared to controls. mutants show the absence of bands at 73 bp and 39 bp in mnli restriction digests of rt-pcr products suggesting that no wild-type allele is being expressed.
Exp Paradigm: Semi-quantitative pcr (qrt-pcr)
Description: Mutants show increased frequency of seizures compared to controls.
Exp Paradigm: Audiogenic seizures were observed: seizures in response to transient environmental noise.
Description: Mutants show a sudden death phenotype compared to controls. mutants died due to audiogenic seizure. three mosaic mutant mice survived to 29, 32 and 35 days.
Exp Paradigm: NA
Description: Gait was assessed as part of ambulation at developmental age P10, and as part of the neuroscore paradigm at P14-P28. Homozygous mutants showed impairments in gait in these assessments.
Description: Kyphosis is a defect in spinal curvature that was used as part of the neuroscore paradigm. In homozygous mutants kyphosis developed at around P18.
Description: Homozygous mutants show a significant decrease of EEF1A2 protein in brain and muscle tissue, and a trend of reduced expression in the heart.
Description: Heterozygous mutants showed a decrease in REM bout frequency, but no change in REM latency or REM bout duration, compared to wildtype mice.
Description: The ledge test was part of the neuroscore paradigm. Heterozygous mutants showed impairments in this test which contribute to their neuroscore.
Description: Gait was assessed as part of ambulation at developmental age P10, and as part of the neuroscore paradigm at P14-P28. Heterozygous mutants showed small impairments in gait in these assessments, reaching significance for males at P10, and contributing to the neuroscore at P14-P28.
Electroencephalogram (EEG): signature of seizure/epilepsy1
Increased
Description: Two putative EEG abnormalities (cortical spike trains and generalized spikes) were noted during vigilance state classification. Cortical spike trains (CSTs) are brief and relatively high-amplitude synchronous sharp polyspikes (â?¼7 Hz spiking frequency) in the motor and somatosensory areas, with occasional generalization into the parietal cortex. CSTs were observed in all six heterozygous mice recorded, with a mean incidence of approximately six events per hour. The incidence of generalized spiking was significantly higher in heterozygous mice compared to wildtype mice.
