Elucidation of synaptic dysfunctions in patients with developmental disorder

• Project/Area Number: 15K09631
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Yamamoto Toshiyuki 東京女子医科大学, 医学部, 教授 (20252851)
• Co-Investigator(Renkei-kenkyūsha): SHIMOJIMA Keiko 東京女子医科大学, 医学部, 特任助教 (30578935)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ヒトiPS細胞 / シナプス機能 / 発達障害 / 遺伝子ノックダウン / ゲノム編集

Outline of Final Research Achievements

Genomic analysis studies on patients with developmental disorders have led the synaptic dysfunction to be considered the essence of the disorder. However, it is almost always that synaptic pathology is suspected from genomic information, and the actual state of molecular pathology at the cell level is hardly understood yet. Therefore, we analyzed the pathological condition at the level of neurons differentiated from human iPS cells and attempted to clarify the molecular dysfunction and its pathology. As a result, it was shown that gene knockdown reduces spine density in neuronal dendrites. We are planning to investigate whether this phenomenon can be rescued by drug administration in the future.

Research Products

• [Journal Article] Possible genes responsible for developmental delay observed in patients with rare 2q23q24 microdeletion syndrome: literature review and description of an additional patient (2017)
  • Author(s): Shimojima K, Okamoto N, Yamamoto T
  • Journal Title: Congenit Anom Volume: in press
  • NAID: 130008142363
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] An Xq22.1q22.2 nullisomy in a male patient with severe neurological impairment. (2017)
  • Author(s): Shirai K, Higashi Y, Shimojima K, Yamamoto T.
  • Journal Title: Am J Med Genet A. Volume: 173(4) Issue: 4 Pages: 1124-1127
  • DOI: 10.1002/ajmg.a.38134
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Aspartylglucosaminuria caused by a novel homozygous mutation in the AGA gene was identified by an exome-first approach in a patient from Japan. (2017)
  • Author(s): Yamamoto T, Shimojima K, Matsufuji M, Mashima R, Sakai E, Okuyama T.
  • Journal Title: Brain Dev. Volume: 39(5) Issue: 5 Pages: 422-425
  • DOI: 10.1016/j.braindev.2016.12.004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mandibulofacial dysostosis with microcephaly: A case presenting with seizures (2017)
  • Author(s): Matsuo M, Yamauchi A, Ito Y, Sakauchi M, Yamamoto T, Okamoto N, Tsurusaki Y, Miyake N, Matsumoto N, Saito K.
  • Journal Title: Brain Dev. Volume: 39(2) Issue: 2 Pages: 177-181
  • DOI: 10.1016/j.braindev.2016.08.008
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Concurrent occurrence of an inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving MAP2K2 in a patient with developmental delay, distinctive facial features, and lambdoid synostosis. (2016)
  • Author(s): Shimojima K, Ondo Y, Matsufuji M, Sano N, Tsuru H, Oyoshi T, Higa N, Tokimura H, Arita K, Yamamoto T.
  • Journal Title: Eur J Med Genet. Volume: 59(11) Issue: 11 Pages: 559-563
  • DOI: 10.1016/j.ejmg.2016.10.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel TUBB3 mutation in a sporadic patient with asymmetric cortical dysplasia (2015)
  • Author(s): Shimojima K, Okamoto N, Yamamoto T.
  • Journal Title: Am J Med Genet A Volume: 170A Issue: 4 Pages: 1076-1079
  • DOI: 10.1002/ajmg.a.37545
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Loss-of-function mutations of STXBP1 in patients with epileptic encephalopathy. (2015)
  • Author(s): Yamamoto T, Shimojima K, Yano T, Ueda Y, Takayama R, Ikeda H, Imai K.
  • Journal Title: Brain Dev Volume: 38 Issue: 3 Pages: 280-284
  • DOI: 10.1016/j.braindev.2015.09.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel PLA2G6 mutations associated with an exonic deletion due to non-allelic homologous recombination in a patient with infantile neuroaxonal dystrophy. (2015)
  • Author(s): Yamamoto T, Shimojima K, Shibata T, Akiyama M, Oka M, Akiyama T, Yoshinaga H, Kobayashi K.
  • Journal Title: Human Genome Variation Volume: 2 Issue: 1 Pages: 15048-15048
  • DOI: 10.1038/hgv.2015.48
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Characteristics of patients with benign partial epilepsy in infancy without PRRT2 mutations. (2015)
  • Author(s): Sangu N, Shimojima K, Okumura A, Ando T, Yamamoto T.
  • Journal Title: Epilepsy Res Volume: 118 Pages: 10-13
  • DOI: 10.1016/j.eplepsyres.2015.09.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Recurrent occurrences of CDKL5 mutations in patients with epileptic encephalopathy. (2015)
  • Author(s): Yamamoto T, Shimojima K, Kimura N, Mogami Y, Usui D, Takayama R, Ikeda H, Imai K.
  • Journal Title: Human Genome Variation Volume: 2 Issue: 1 Pages: 15042-15042
  • DOI: 10.1038/hgv.2015.42
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Neuro-functional analysis using disease-specific iPS cells (2017)
  • Author(s): Yamamoto T, Shimojima K
  • Organizer: Bulletin of the Japanese Sciety for Neurochemistry
• [Presentation] Genetic basis of benign infantile epilepsy. (2015)
  • Author(s): Yamamoto T
  • Organizer: International Symposium on Benign Infantile Seizures (ISBIS), The 17th Annual Meeting of Infantile Seizure Society
  • Place of Presentation: National Center of Sciences Building (Tokyo, Japan)
  • Year and Date: 2015-09-25
  • Int'l Joint Research / Invited