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

• Published in: Human mutation Vol. 39; no. 7; pp. 934 - 938
• Main Authors: Mignon‐Ravix, Cécile, Milh, Mathieu, Kaiser, Charlotte Sophia, Daniel, Jens, Riccardi, Florence, Cacciagli, Pierre, Nagara, Majdi, Busa, Tiffany, Liebau, Eva, Villard, Laurent
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01.07.2018; Wiley
• Subjects: Adult; Consanguinity; early myoclonic epilepsy; Encephalopathy; Epilepsies, Myoclonic - genetics; Epilepsies, Myoclonic - physiopathology; Epilepsy; Epileptic Syndromes - genetics; Epileptic Syndromes - physiopathology; Female; Genetic Predisposition to Disease; Genetics; Homozygote; Human genetics; Humans; Infant, Newborn; Life Sciences; Male; Mutation, Missense - genetics; Neonates; Neural networks; Ohtahara syndrome; Proteins; Spasms, Infantile - genetics; Spasms, Infantile - physiopathology; Translation; UBA5; Ubiquitin; Ubiquitin-Activating Enzymes - genetics; Whole Exome Sequencing; Ohtahara syndrome; early myoclonic epilepsy; encephalopathy; UBA5
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.23534

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. We identified a homozygous missense variant in the UBA5 gene in a patient with early myoclonic epilepsy (EME), the most severe epileptic syndromes affecting neonates. We showed that the mutation severely affect protein function. These findings underline the critical role of UBA5 for normal neuronal networks activity and provide a new molecular cause to EME.