Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy

2015 Fiscal Year Final Research Report

• Project/Area Number: 26860816
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Yokohama City University
• Principal Investigator: KODERA Hirofumi 横浜市立大学, 医学(系)研究科(研究院), 博士研究員 (70637884)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: てんかん性脳症 / 全エクソーム解析 / QARS / アミノアシルtRNA合成酵素 / アミノアシル化

Outline of Final Research Achievements

Using whole exome sequencing, we identified compound heterozygous mutations [c.169T>C (p.Tyr57His) and c.1485dup (p.Lys496*)] in QARS, which encodes glutaminyl-tRNA synthetase, in two siblings with early-onset epileptic encephalopathy (EOEE).
Recessive mutations in QARS, including the loss-of-function missense mutation p.Tyr57His, have been reported to cause intractable seizures with progressive microcephaly. The p.Lys496* mutation is novel and causes truncation of the QARS protein, leading to a deletion of part of the catalytic domain and the entire anticodon-binding domain. Transient expression of the p.Lys496* mutant in neuroblastoma 2A cells revealed diminished and aberrantly aggregated expression, indicating the loss-of-function nature of this mutant. Together with the previous report, our data suggest that abnormal aminoacylation is one of the underlying pathologies of EOEE.

Free Research Field

人類遺伝学