ArticleHuman molecular genetics2012
A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity and increased susceptibility to proteostatic insult.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 71 citations in OpenAlex.
- How Early Should I Refer My Patient? The Benefits of a Quick Ophthalmic Referral in Spinocerebellar Ataxias, a Case Series and Literature Review.Brain sciences · 2026Article
- From chromatin to proteostasis: multilevel gene regulation in Mendelian diseases.Frontiers in epigenetics and epigenomics · 2026Review
- Missense variant in TTBK2 kinase domain causes loss of function and impaired protein phosphorylation.Scientific reports · 2025Article
- Guidelines for minimal reporting requirements, design and interpretation of experiments involving the use of eukaryotic dual gene expression reporters (MINDR).Nature structural & molecular biology · 2025Review
- Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.American journal of human genetics · 2025Article
- Extracellular vesicle signatures from eye lavage as novel non-invasive biomarkers for hypoxic ischaemic insult-findings from a neonatal mouse model.Frontiers in medical technology · 2025Article
- Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).Annals of neurology · 2024Article
- Hsp90 and cochaperones have two genetically distinct roles in regulating eEF2 function.PLoS genetics · 2024Article
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- Gelation of cytoplasmic expanded CAG RNA repeats suppresses global protein synthesis.Nature chemical biology · 2023Article
- Expansion of clinical and variant spectrum of EEF2-related neurodevelopmental disorder: Report of two additional cases.American journal of medical genetics. Part A · 2023Article
- Identification ofmSphere · 2023Article
- A novel de novo variant in CASK causes a severe neurodevelopmental disorder that masks the phenotype of a novel de novo variant in EEF2.Journal of human genetics · 2023Article
- Our current understanding of the toxicity of altered mito-ribosomal fidelity during mitochondrial protein synthesis: What can it tell us about human disease?Frontiers in physiology · 2023Review
- eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior.EMBO reports · 2022Article
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- Lysosomal targetomics ofAutophagy · 2022Article
- Spinocerebellar ataxias (SCAs) caused by common mutations.Neurogenetics · 2021Review
- Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan.Aging cell · 2021Article
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Authors and funding
14 authors at 7 institutions in 3 countries.
Funding
Abstract
The autosomal dominant spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders exhibiting cerebellar atrophy and Purkinje cell degeneration whose subtypes arise from 31 distinct genetic loci. Our group previously published the locus for SCA26 on chromosome 19p13.3. In this study, we performed targeted deep sequencing of the critical interval in order to identify candidate causative variants in individuals from the SCA26 family. We identified a single variant that co-segregates with the disease phenotype that produces a single amino acid substitution in eukaryotic elongation factor 2. This substitution, P596H, sits in a domain critical for maintaining reading frame during translation. The yeast equivalent, P580H EF2, demonstrated impaired translocation, detected as an increased rate of -1 programmed ribosomal frameshift read-through in a dual-luciferase assay for observing translational recoding. This substitution also results in a greater susceptibility to proteostatic disruption, as evidenced by a more robust activation of a reporter gene driven by unfolded protein response activation upon challenge with dithiothreitol or heat shock in our yeast model system. Our results present a compelling candidate mutation and mechanism for the pathogenesis of SCA26 and further support the role of proteostatic disruption in neurodegenerative diseases.
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Registered trials
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