Biallelic mutations in the gene encoding eEF1A2 cause seizures and sudden death in F0 mice

Davies, Faith C.J.; Hope, Jilly; McLachlan, Fiona; Nunez, Francis; Doig, Jennifer; Bengani, Hemant; Smith, Colin; Abbott, Catherine M.

doi:10.1038/srep46019

Cited by 28 publications

(29 citation statements)

References 31 publications

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“…Although the effects on gene expression of 6-OHDA and eft-3/4 gene silencing were different, the anti-apoptotic genes were strongly suppressed when both treatments were combined. The previous findings showed that the downregulation of eEF1A1 causes the neurons to be more vulnerable to the external insults (Vera et al, 2014;Davies et al, 2017), and our results further showed that the downregulation of eEF1A2 also increases sensitivity to external insults. Our data encourage the fact that the downregulation of eft-3/4 attenuates the neurons to be more vulnerable to neurotoxin by suppression of the antiapoptotic genes as well as the promotion of some apoptotic gene expressions.…”

Section: Discussionsupporting

confidence: 85%

Downregulation of eEF1A/EFT3-4 Enhances Dopaminergic Neurodegeneration After 6-OHDA Exposure in C. elegans Model

2020

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein protein and selective death of dopaminergic (DA) neurons in the substantia nigra of the midbrain. Although the molecular pathogenesis of PD is not completely understood, a recent study has reported that eukaryotic translation elongation factor 1 alpha (eEF1A) declined in the PD-affected brain. Therefore, the roles of eEF1A1 and eEF1A2 in the prevention of DA neuronal cell death in PD are aimed to be investigated. Herein, by using Caenorhabditis elegans as a PD model, we investigated the role of eft-3/eft-4, the worm homolog of eEF1A1/eEF1A2, on 6-hydroxydopamine (6-OHDA)-induced DA neuron degeneration. Our results demonstrated that the expressions of eft-3 and eft-4 were decreased in the 6-OHDA-induced worms. RNA interference (RNAi) of eft-3 and eft-4 resulted in dramatic exacerbation of DA neurodegeneration induced by 6-OHDA, as well as aggravated the food-sensing behavior, ethanol avoidance, and decreased lifespan when compared with only 6-OHDA-induced worms. Moreover, downregulation of eft-3/4 in 6-OHDA-induced worms suppressed the expression of the anti-apoptotic genes, including PI3K/age-1, PDK-1/pdk-1, mTOR/let-363, and AKT-1,2/akt-1,2, promoting the expression of apoptotic genes such as BH3/egl-1 and Caspase-9/ced-3. Collectively, these findings indicate that eEF1A plays an important role in the 6-OHDA-induced neurodegeneration through the phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase (Akt)/mammalian target of rapamycin (mTOR) pathway and that eEF1A isoforms may be a novel and effective pro-survival factor in protective DA neurons against toxin-induced neuronal death.

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Section: Discussionsupporting

confidence: 85%

Downregulation of eEF1A/EFT3-4 Enhances Dopaminergic Neurodegeneration After 6-OHDA Exposure in C. elegans Model

2020

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“…These observations suggest that heterozygous complete loss‐of‐function variants may be lethal in humans. In null mouse models, complete loss of eEF1A2 is lethal by 28 days and mice exhibit a muscle wasting phenotype with or without seizures, while heterozygous mice display no overt phenotype (Chambers et al, 1998; Davies et al, 2017). Moreover, in small studies, mice carrying a p.Gly70Ser missense variant either in the homozygous state or in combination with a CRISPR‐generated indel on the other allele, were phenotypically indistinguishable from complete null mice (Davies et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…In zebrafish, the expression is limited to the brain (Figure S2). eEF1A2 knockout mice display early‐onset neurodegeneration and muscle wasting (Chambers, Peters, & Abbott, 1998), as well as spontaneous seizures and sudden death in another null mouse model (Davies et al, 2017). In contrast, heterozygous mice are normal (Chambers et al, 1998; Davies et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Damaging de novo missense variants inEEF1A2lead to a developmental and degenerative epileptic‐dyskinetic encephalopathy

Carvill

Helbig

Myers³

et al. 2020

Human Mutation

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Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein‐damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic‐dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.

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“…Concentration of protein lysates was determined using either the Pierce BCA protein assay kit (Pierce) or the DC Protein Assay (Bio-Rad) following the manufacturers' instructions. Western blotting was carried out using near-infrared detection method by LI-COR as previously described in [36]. Protein detection was also performed using the chemiluminescence method.…”

Section: Protein Analysismentioning

confidence: 99%

Translation elongation factor 1A2 is encoded by one of four closely related eef1a genes and is dispensable for survival in zebrafish

2020

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Zebrafish are valuable model organisms for the study of human single-gene disorders: they are genetically manipulable, their development is well understood, and mutant lines with measurable, disease-appropriate phenotypic abnormalities can be used for high throughput drug screening approaches. However, gene duplication events in zebrafish can result in redundancy of gene function, masking loss-of-function phenotypes and thus confounding this approach to disease modelling. Furthermore, recent studies have yielded contrasting results depending on whether specific genes are targeted using genome editing to make mutant lines, or whether morpholinos are used (morphants). De novo missense mutations in the human gene EEF1A2, encoding a tissue-specific translation elongation factor, cause severe neurodevelopmental disorders; there is a real need for a model system to study these disorders and we wanted to explore the possibility of a zebrafish model. We identified four eef1a genes and examined their developmental and tissue-specific expression patterns: eef1a1l1 is first to be expressed while eef1a2 is only detected later during development. We then determined the effects of introducing null mutations into translation elongation factor 1A2 (eEF1A2) in zebrafish using CRISPR/Cas9 gene editing, in order to compare the results with previously described morphants, and with severe neurodegenerative lethal phenotype of eEF1A2-null mice. In contrast with both earlier analyses in zebrafish using morpholinos and with the mouse eEF1A2-null mice, disruption of the eef1a2 gene in zebrafish is compatible with normal lifespan. The resulting lines, however, may provide a valuable platform for studying the effects of expression of mutant human eEF1A2 mRNA.

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Biallelic mutations in the gene encoding eEF1A2 cause seizures and sudden death in F0 mice

Cited by 28 publications

References 31 publications

Downregulation of eEF1A/EFT3-4 Enhances Dopaminergic Neurodegeneration After 6-OHDA Exposure in C. elegans Model

Downregulation of eEF1A/EFT3-4 Enhances Dopaminergic Neurodegeneration After 6-OHDA Exposure in C. elegans Model

Damaging de novo missense variants inEEF1A2lead to a developmental and degenerative epileptic‐dyskinetic encephalopathy

Translation elongation factor 1A2 is encoded by one of four closely related eef1a genes and is dispensable for survival in zebrafish

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