Elucidation of molecular bases of brain diseases based on personal genome information

• Project Area: Personal genome-based initiatives toward understanding bran diseases
• Project/Area Number: 22129002
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: TSUJI Shoji 東京大学, 医学部附属病院, 教授 (70150612)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥403,260,000 (Direct Cost: ¥310,200,000、Indirect Cost: ¥93,060,000); Fiscal Year 2014: ¥74,100,000 (Direct Cost: ¥57,000,000、Indirect Cost: ¥17,100,000); Fiscal Year 2013: ¥77,740,000 (Direct Cost: ¥59,800,000、Indirect Cost: ¥17,940,000); Fiscal Year 2012: ¥81,510,000 (Direct Cost: ¥62,700,000、Indirect Cost: ¥18,810,000); Fiscal Year 2011: ¥80,730,000 (Direct Cost: ¥62,100,000、Indirect Cost: ¥18,630,000); Fiscal Year 2010: ¥89,180,000 (Direct Cost: ¥68,600,000、Indirect Cost: ¥20,580,000)
• Keywords: ゲノム / 個人ゲノム / 脳疾患 / インフォマティクス / シーケンサー / ゲノムインフォマティクス

Outline of Final Research Achievements

Applying comprehensive genome sequencing with next generation sequencers, we conducted molecular genetics studies to elucidate molecular bases of hereditary neurodegenerative diseases as well as sporadic neurodegenerative diseases. We discovered the causative gene (TFG) for Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). We also discovered the causative gene (ERBB4) for familial amyotrophic lateral sclerosis (ALS19). Regarding sporadic neurodegenerative diseases, we discovered that COQ2 is the causative gene for familial multiple system atrophy (MSA), and furthermore, multiple rare variants of COQ2 increase the risk for developing sporadic MSA.

Research Products

• [Journal Article] Novel mutations in the PNPLA6 gene in Boucher-Neuhäuser syndrome. (2015)
  • Author(s): Takiyama Y, Koh K, Kobayashi F, Miwa M, Shindo K, Isozaki E, Ishiura H, and Tsuji S.
  • Journal Title: J Hum Genet Volume: in press Issue: 4 Pages: 217-220
  • DOI: 10.1038/jhg.2015.3
  • Peer Reviewed
• [Journal Article] Variants associated with Gaucher disease in multiple system atrophy (2015)
  • Author(s): Mitsui J, Matsukawa T, Sasaki H, (中略), Tsuji S.
  • Journal Title: Ann Clin Transl Neurol Volume: 2 Issue: 1 Pages: 59-63
  • DOI: 10.1002/acn3.18
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genotype-Phenotype Correlations in Alternating Hemiplegia of Childhood (2014)
  • Author(s): Sasaki M, Ishii A, Saito Y, (中略）, Tsuji S and Hirose S.
  • Journal Title: Neurology Volume: 82 Issue: 6 Pages: 482-490
  • DOI: 10.1212/wnl.0000000000000102
  • Peer Reviewed
• [Journal Article] Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing. (2014)
  • Author(s): Doi K, Monjo T, Hoang PH, Yoshimura J, Yurino H, Mitsui J, Ishiura H, Takahashi Y, Ichikawa Y, Goto J, Tsuji S, Morishita S.
  • Journal Title: Bioinformatics Volume: 30 Issue: 6 Pages: 815-822
  • DOI: 10.1093/bioinformatics/btt647
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses. (2014)
  • Author(s): Ishiura H, Takahashi Y, Hayashi T, Saito K, Furuya H, Watanabe M, Murata M, Suzuki M, Sugiura A, Sawai S, Shibuya K, Ueda N, Ichikawa Y, Kanazawa I, Goto J and Tsuji S
  • Journal Title: J Hum Genet Volume: 59 Issue: 3 Pages: 163-172
  • DOI: 10.1038/jhg.2013.139
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Exome sequencing shows a novel de novo mutation in ATL1. (2014)
  • Author(s): Koh K, Ishiura H, Miwa M, Doi K, Yoshimura J, Mitsui J, Goto J, Morishita S, Tsuji S and Takiyama Y.
  • Journal Title: Neurology and Clinical Neuroscience Volume: 2 Issue: 1 Pages: 1-4
  • DOI: 10.1111/ncn3.72
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genomic Aspects of Sporadic Neurodegenerative Diseases. (2014)
  • Author(s): Mitsui J and Tsuji S.
  • Journal Title: Biochem Biophys Res Commun Volume: 452 Issue: 2 Pages: 221-225
  • DOI: 10.1016/j.bbrc.2014.07.098
  • Peer Reviewed / Open Access
• [Journal Article] Neurogenomics view of neurological diseases. (2013)
  • Author(s): Tsuji S.
  • Journal Title: Arch. Neurol. Volume: 70 Pages: 689-694
  • Peer Reviewed
• [Journal Article] Exome analysis reveals a Japanese family with spinocerebellar ataxia, autosomal recessive 1. (2013)
  • Author(s): Ichikawa Y, Ishiura H, Mitsui J, Takahashi Y, Kobayashi S, Takuma H, Kanazawa I, Doi K, Yoshimura J, Morishita S, Goto J, Tsuji S
  • Journal Title: J. Neurol. Sci. Volume: 331 Issue: 1-2 Pages: 158-160
  • DOI: 10.1016/j.jns.2013.05.018
  • Peer Reviewed
• [Journal Article] ERBB4 Mutations that Disrupt the Neuregulin-ErbB4 Pathway Cause Amyotrophic Lateral Sclerosis Type 19. (2013)
  • Author(s): Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A, (33名省略）, Morishita S, Goto J and Tsuji S.
  • Journal Title: Am J Hum Genet Volume: 93 Issue: 5 Pages: 900-905
  • DOI: 10.1016/j.ajhg.2013.09.008
  • Peer Reviewed
• [Journal Article] Mutations in COQ2 in familial and sporadic multiple-system atrophy. (2013)
  • Author(s): Mitsui J, et. al.
  • Journal Title: N Engl J Med Volume: 369 Issue: 3 Pages: 233-244
  • DOI: 10.1056/nejmoa1212115
  • Peer Reviewed
• [Journal Article] The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement. (2012)
  • Author(s): Ishiura H
  • Journal Title: Am J Hum Genet. Volume: 91(2) Issue: 2 Pages: 320-9
  • DOI: 10.1016/j.ajhg.2012.07.014
  • Peer Reviewed
• [Journal Article] CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy. (2012)
  • Author(s): Mitsui J, Matsukawa T, Ishiura H, Higasa K, Yoshimura J, Saito TL, Ahsan B, Takahashi Y, Goto J, Iwata A, Niimi Y, Riku Y, Goto Y, Mano K, Yoshida M, Morishita S, Tsuji S.
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet. Volume: 159B(8) Issue: 8 Pages: 951-7
  • DOI: 10.1002/ajmg.b.32100
  • Peer Reviewed
• [Journal Article] Identification of novel SNPs of ABCD1, ABCD2, ABCD3 and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes (2011)
  • Author(s): Matsukawa T, Asheuer M, Takahashi Y, Goto J, Suzuki Y, Shimozawa N, Takano H, Onodera O, Nishizawa M, Aubourg P, Tsuji S
  • Journal Title: Neurogenetics Volume: 12 Pages: 41-50
  • Peer Reviewed
• [Journal Article] Posterior column ataxia with retinitis pigmentosa in a Japanese family with a novel mutation in FLVCR1 (2011)
  • Author(s): Ishiura H, Fukuda Y, Mitsui J, Nakahara Y, Ahsan B, Takahashi Y, Ichikawa Y, Goto J, Sakai T, Tsuji S
  • Journal Title: Neurogenetics Volume: 12 Pages: 117-121
  • Peer Reviewed
• [Journal Article] Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5 (2011)
  • Author(s): Matsukawa T, Wang X, Liu R, Onuki Y, Kubota A, Hida A, Kowa H, Fukuda Y, Ishiura H, Mitsui J, Takahashi Y, Aoki S, Takizawa T, Shimizu J, Goto J, Proud CG, Tsuji S
  • Journal Title: Neurogenetics Volume: 12 Pages: 259-261
  • Peer Reviewed
• [Journal Article] Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing employing next-generation sequencer (2010)
  • Author(s): Mitsui J, Fukuda Y, Azuma K, Tozaki H, Ishiura H, Takahashi Y, Goto J, Tsuji S
  • Journal Title: J.Hum.Genet. Volume: 55 Pages: 448-455
  • Peer Reviewed
• [Journal Article] Genetics of neurodegenerative diseases : insights from high-throughput resequencing (2010)
  • Author(s): Tsuji S.
  • Journal Title: Hum.Mol.Genet. Volume: 19 Pages: 65-70
  • Peer Reviewed
• [Journal Article] Mechanisms of genomic instabilities underlying two common fragile site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines (2010)
  • Author(s): Mitsui J, Takahashi Y, Goto J, Tomiyama H, Ishikawa S, Yoshino H, Minami N, Smith DI, Lesage S, Aburatani H, Nishino I, Brice I, Hattori N, Tsuji S
  • Journal Title: Amer J Hum Genet Volume: 87 Pages: 75-89
  • Peer Reviewed
• [Presentation] The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). (2012)
  • Author(s): Ishiura, H. 他29名，Tsuji, S.
  • Organizer: American Society of Human Genetics
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2012-11-06
• [Remarks] 筋萎縮性側索硬化症の新たな原因遺伝子を発見・根本治療への手がかりを得る
  • URL: http://www.h.u-tokyo.ac.jp/press/press_archive/20131011.html
• [Remarks] 新しい運動ニューロン病の原因遺伝子を発見
  • URL: http://www.h.u-tokyo.ac.jp/press/press_archives/20120810.html
• [Remarks] 新しい運動ニューロン病の原因遺伝子を発見
  • URL: http://www.h.u-tokyo.ac.jp/vcms_lf/release_20120803.pdf
• [Patent(Industrial Property Rights)] 筋萎縮性側索硬化症の新規病因遺伝子 (2013)
  • Inventor(s): 辻 省次，高橋 祐二
  • Industrial Property Rights Holder: 辻 省次，高橋 祐二
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-08-02
  • Overseas