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Abnormal function of the UBA5 protein in a case of early developmental and epileptic encephalopathy with suppression-burst.

Cécile Mignon-RavixMathieu MilhCharlotte Sophia KaiserJens DanielFlorence RiccardiPierre CacciagliMajdi NagaraTiffany BusaEva LiebauLaurent Villard
Published in: Human mutation (2018)
Early myoclonic epilepsy (EME) or Aicardi syndrome is one of the most severe epileptic syndromes affecting neonates. We performed whole exome sequencing in a sporadic case affected by EME and his parents. In the proband, we identified a homozygous missense variant in the ubiquitin-like modifier activating enzyme 5 (UBA5) gene, encoding a protein involved in post-translational modifications. Functional analysis of the UBA5 variant protein reveals that it is almost completely unable to perform its trans-thiolation activity. Although recessive variants in UBA5 have recently been associated with epileptic encephalopathy, variants in this gene have never been reported to cause EME. Our results further demonstrate the importance of post-translational modifications such as the addition of an ubiquitin-fold modifier 1 (UFM1) to target proteins (ufmylation) for normal neuronal networks activity, and reveal that the dysfunction of the ubiquitous UBA5 protein is a cause of EME.
Keyphrases
  • copy number
  • protein protein
  • early onset
  • genome wide
  • amino acid
  • small molecule
  • binding protein
  • oxidative stress
  • single cell
  • high frequency
  • case report
  • low birth weight
  • brain injury
  • muscular dystrophy