Damaging de novo missense variants inEEF1A2lead to a developmental and degenerative epileptic‐dyskinetic encephalopathy
- 20 March 2020
- journal article
- research article
- Published by Hindawi Limited in Human Mutation
- Vol. 41 (7), 1263-1279
- https://doi.org/10.1002/humu.24015
Abstract
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.Keywords
Funding Information
- NIH/NINDS
- NHRMC
- Doris Duke
This publication has 51 references indexed in Scilit:
- Genic Intolerance to Functional Variation and the Interpretation of Personal GenomesPLoS Genetics, 2013
- Exome sequencing reveals new causal mutations in children with epileptic encephalopathiesEpilepsia, 2013
- Evidence That Eukaryotic Translation Elongation Factor 1A (eEF1A) Binds the Gcn2 Protein C Terminus and Inhibits Gcn2 Activity*Journal of Biological Chemistry, 2011
- Autophagy and the Integrated Stress ResponseMolecular Cell, 2010
- Structural Models of Human eEF1A1 and eEF1A2 Reveal Two Distinct Surface Clusters of Sequence Variation and Potential Differences in PhosphorylationPLOS ONE, 2009
- Translation Elongation Factor eEF1A2 Is Essential for Post-weaning Survival in MiceJournal of Biological Chemistry, 2007
- Improper Organization of the Actin Cytoskeleton Affects Protein Synthesis at InitiationMolecular and Cellular Biology, 2007
- Chaperone-like activity of mammalian elongation factor eEF1A: renaturation of aminoacyl-tRNA synthetasesThe International Journal of Biochemistry & Cell Biology, 2004
- Immuno-characterization of the switch of peptide elongation factors eEF1A-1/EF-1α and eEF1A-2/S1 in the central nervous system during mouse developmentDevelopmental Brain Research, 2004
- Sequence and structure-based prediction of eukaryotic protein phosphorylation sitesJournal of Molecular Biology, 1999