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

• 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
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• 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.

Research Products

• [Journal Article] De novo GABRA1 mutations in Ohtahara and West syndromes (2015)
  • Author(s): ○Hirofumi Kodera, et al, Hirotomo Saitsu and Naomichi Matsumoto
  • Journal Title: Epilepsia Volume: 57 Issue: 4 Pages: 566-573
  • DOI: 10.1111/epi.13344
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy. (2015)
  • Author(s): Kodera H, Osaka H, Iai M, Aida N, Yamashita A, Tsurusaki Y, Nakashima M, Miyake N, Saitsu H, Matsumoto N.
  • Journal Title: J Hum Genet. Volume: 60(2) Issue: 2 Pages: 97-101
  • DOI: 10.1038/jhg.2014.103
  • Peer Reviewed / Open Access
• [Journal Article] GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders (2015)
  • Author(s): Ohba C, Shiina M, Tohyama J, Haginoya K, Lerman-Sagie T, Okamoto N, Blumkin L, Lev D, Mukaida S, Nozaki F, Uematsu M, Onuma A, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Kato M, Ogata K, Saitsu H, Matsumoto N
  • Journal Title: Epilepsia Volume: 印刷中 Issue: 6 Pages: 841-848
  • DOI: 10.1111/epi.12987
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] De novo KCNT1 mutations in early-onset epileptic encephalopathy. (2015)
  • Author(s): Ohba C, Kato M, Takahashi N, Osaka H, Shiihara T, Tohyama J, Nabatame S, Azuma J, Fujii Y, Hara M, Tsurusawa R, Inoue T, Ogata R, Watanabe Y, Togashi N, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Saitsu H, Matsumoto N.
  • Journal Title: Epilepsia Volume: 56(9) Issue: 9
  • DOI: 10.1111/epi.13072
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in COG2 encoding a subunit of the conserved oligomeric golgi complex cause a congenital disorder of glycosylation (2015)
  • Author(s): 17.Kodera H, Ando N, Yuasa I, Wada Y, Tsurusaki Y, Nakashima M, Miyake N, Saitoh S, Matsumoto N, Saitsu H
  • Journal Title: Clin Genet Volume: 87 Issue: 5 Pages: 455-460
  • DOI: 10.1111/cge.12417
  • Peer Reviewed
• [Journal Article] De novo SOX11 mutations cause Coffin-Siris syndrome (2014)
  • Author(s): Tsurusaki Y, Ohashi H, Phadke S, Koshimizu E, Kou I, Shiina M, Suzuki T, Okamoto N, Imamura S, Yamashita M, Watanabe S, Yoshiura K-i, Kodera H, Miyatake S, Nakashima N, Saitsu H, Ogata K, Ikegawa S, Miyake N, and Matsumoto N.
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 4011-4011
  • DOI: 10.1038/ncomms5011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PIGO mutations in intractable epilepsy and severe developmental delay with mild elevation of alkaline phosphatase levels. (2014)
  • Author(s): Nakamura, K.Osaka, H.Murakami, Y.Anzai, R.Nishiyama, K.Kodera, H.Nakashima, M.Tsurusaki, Y.Miyake, N.Kinoshita, T.Matsumoto, N. and Saitsu, H
  • Journal Title: Epilepsia Volume: 55 Issue: 2 Pages: 13-17
  • DOI: 10.1111/epi.12508
  • Peer Reviewed
• [Journal Article] AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes (2014)
  • Author(s): Nakamura K, Kato M, Tohyama J, Shiohama T, Hayasaka K, Nishiyama K, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Matsumoto N, Saitsu H.
  • Journal Title: Clin Genet Volume: 85（4） Issue: 4 Pages: 396-398
  • DOI: 10.1111/cge.12188
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 先天性糖鎖合成異常症の新規原因遺伝子COG2の同定 (2014)
  • Author(s): 小寺啓文、安藤直樹、湯浅勲、和田芳直、鶴崎美徳、中島光子、三宅紀子、齋藤伸治、松本直通、才津浩智
  • Organizer: 第59回日本人類遺伝学会
  • Place of Presentation: タワーホール船堀（東京都江戸川区）
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] Mutations in COG2 encoding a subunit of the conserved oligomeric golgi complex cause a congenital disorder of glycosylation (2014)
  • Author(s): Kodera H, Ando N, Yuasa I, Wada Y, Tsurusaki Y, Nakashima M, Miyake N, Saitoh S, Matsumoto N, Saitsu H.
  • Organizer: The American Society of Human Genetics 64th Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-10-18 – 2014-10-22