Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic‐dyskinetic encephalopathy - Sorbonne Université Access content directly
Journal Articles Human Mutation Year : 2020

Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic‐dyskinetic encephalopathy

Katherine Helbig
Candace Myers
  • Function : Author
Keri Ramsey
  • Function : Author
Vinodh Narayanan
  • Function : Author
Timothy Feyma
  • Function : Author
Luis Rohena
  • Function : Author
Georgina Hollingsworth
  • Function : Author
Deepak Gill
  • Function : Author
Lynette Sadleir
  • Function : Author
Angela Lin
  • Function : Author
Tjitske Kleefstra
  • Function : Author
David Raible
  • Function : Author
Evelyn Sattlegger
  • Function : Author
Heather Mefford
  • Function : Author

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.

Dates and versions

hal-04585234 , version 1 (23-05-2024)

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Cite

Gemma Carvill, Katherine Helbig, Candace Myers, Marcello Scala, Robert Huether, et al.. Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic‐dyskinetic encephalopathy. Human Mutation, 2020, 41 (7), pp.1263-1279. ⟨10.1002/humu.24015⟩. ⟨hal-04585234⟩
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