遺伝性痙性対麻痺と紀伊筋萎縮性側索硬化症・パーキンソン認知症複合の遺伝子解析研究

• Project/Area Number: 10J05639
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Neurology
• Research Institution: The University of Tokyo
• Principal Investigator: 石浦 浩之 東京大学, 医学部附属病院, 特別研究員(PD)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2011: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2010: ¥700,000 (Direct Cost: ¥700,000)
• Keywords: 遺伝性痙性対麻痺 / 紀伊筋萎縮性側索硬化症 / 遺伝子解析 / C90RF72 / SNPタイピング / 連鎖解析

Research Abstract

遺伝性痙性対麻痺:に関しては、SPG12に関する国際共同研究に参画し、遺伝子同定に寄与することができた(Montenegro G,Ishiura H,et al,J Clin Invest 2012)。また、リソース収集を進め、引き続き遺伝性痙性対麻痺の分子病態の解明を進める予定である。
紀伊筋萎縮性側索硬化症・パーキンソン認知症複合(ALS/PDC)に関しては、紀伊半島の最南端のALS3症例においてC90RF72内の6塩基反復配列の伸長を認め、9番染色体に連鎖する筋萎縮性側索硬化症であることが判明した。本地域における9番染色体に連鎖する筋萎縮性側索硬化症の頻度は、本邦の他の地域(Majounie E,Ishiura H et al. 2012)に比較して有意に頻度が高いことを見出し、紀伊半島におけるALSの高罹病率を部分的に説明できると考えられた(Ishiura H,et al.Archives of Neurology in press)。その他、紀伊半島最南端地域においてはOPTNのヘテロ接合性新規アミノ酸置換を持つALS症例も見出したが、他のALS症例においては観察されず、病原性については検討の余地が残った(Naruse H,Ishiura H,et al.Amyotroph Lateral Scler in press)。パーキンソン認知症複合(PDC)に関しては、本研究では遺伝子同定には至らず、今後の研究が必要であると考えられた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

紀伊筋萎縮性側索硬化症に関して、紀南地方においてC90RF72内の6塩基異常伸長が高頻度に見られることを見出し、論文として報告することができた。遺伝性痙性対麻痺に関してはSPG12の原因遺伝子同定に関する国際共同研究に参画し、論文として発表することができた。

Strategy for Future Research Activity

紀伊筋萎縮性側索硬化症に関しては、C90RF72内の6塩基異常伸長の無い症例に関する遺伝学的基盤の解明を進める必要がある。遺伝性痙性対麻痺に関しては、さらに原因遺伝子を同定していく努力が必要である。

Research Products

• [Journal Article] Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12 (2012)
  • Author(s): Montenegro G, Ishiura H, et al
  • Journal Title: J Clin Invest Volume: 122 Issue: 2 Pages: 538-544
  • DOI: 10.1172/jci60560
  • Peer Reviewed
• [Journal Article] Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease (2012)
  • Author(s): Maeda MH, Ishiura H, et al
  • Journal Title: Ann Neurol Volume: 71 Issue: 1 Pages: 84-92
  • DOI: 10.1002/ana.22658
  • Peer Reviewed
• [Journal Article] Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia : a cross sectional study (2012)
  • Author(s): Majounie E, Ishiura H, et al
  • Journal Title: Lancet Neurol Volume: 11 Issue: 4 Pages: 323-330
  • DOI: 10.1016/s1474-4422(12)70043-1
  • Peer Reviewed
• [Journal Article] C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis in the Kii peninsula of Japan (2012)
  • Author(s): Ishiura H, et al
  • Journal Title: Arch Neurol Volume: (In press)
  • Peer Reviewed
• [Journal Article] Mutational analysis of familial and sporadic amyotrophic lateral sclerosis with OPTN mutations in Japanese population (2012)
  • Author(s): Naruse H, Ishiura H, et al
  • Journal Title: Amyotroph Lateral Scler Volume: (In press)
  • 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, et al
  • Journal Title: Neurogenetics Volume: 12 Issue: 2 Pages: 117-121
  • DOI: 10.1007/s10048-010-0271-4
  • 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, Ishiura H, et al
  • Journal Title: Neurogenetics Volume: 12 Issue: 3 Pages: 259-261
  • DOI: 10.1007/s10048-011-0284-7
  • 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: In press(掲載確定)
  • Peer Reviewed
• [Journal Article] 遺伝性痙性対麻痺の分子遺伝学と遺伝子診断. (2011)
  • Author(s): 石浦浩之
  • Journal Title: 神経内科 Volume: 74 Pages: 146-151
• [Journal Article] 臨床医学への展望2011-血管系を除く- (2011)
  • Author(s): 辻省次(分担共著)
  • Journal Title: 日本医事新報 Volume: 4533 Pages: 146-151
• [Journal Article] Multiplexed resequencing analysis to identify rare variants in pooled DNA with barcode indexing using next-generation sequencer (2010)
  • Author(s): Mitsui J, Fukuda Y, Azuma K, Tozaki H, Ishiura H, Takahashi Y, Goto J, Tsuji S.
  • Journal Title: Journal of Human Genetics Volume: 55 Pages: 448-455
  • Peer Reviewed
• [Journal Article] A case of atypical amyloid polyneuropathy with predominant upper-limb involvement with the diagnosis unexpectedly found at lung operation. (2010)
  • Author(s): Shirota Y, Iwata A, Ishiura H, Hashimoto M, Goto J, Shimizu J, Hanajima R, Nakajima J, Takazawa Y, Tsuji S.
  • Journal Title: Internal medicine Volume: 49 Pages: 1627-1631
  • Peer Reviewed
• [Journal Article] Dominant mutations in RP1L1 are responsible for occult macular dystrophy. (2010)
  • Author(s): Akahori M, Tsunoda K, Miyake Y, Fukuda Y, Ishiura H, Tsuji S, Usui T, Hatase T, Nakamura M, Ohde H, Itabashi T, Okamoto H, Takada Y, Iwata T.
  • Journal Title: American Journal of Human Genetics Volume: 87 Pages: 424-429
  • Peer Reviewed
• [Journal Article] 臨床医学への展望2010-血管系を除く- (2010)
  • Author(s): 辻省次(分担共著)
  • Journal Title: 日本医事新報 Volume: 4484 Pages: 46-59
• [Presentation] Massively parallel sequence analysis reveals the causative gene of posterior column ataxia with retinitis pigmentosa (2011)
  • Author(s): Ishiura H, et al
  • Organizer: 61^<st> Annual meeting of American Society of Human Genetics/12^<th> International Conference on Human Genetics
  • Place of Presentation: モントリオール、カナダ
  • Year and Date: 2011-10-12
• [Presentation] Massively parallel sequence analysis reveals the causative gene of an autosomal recessive neurodegenerative disorder, posterior column ataxia with retinitis pigmentosa (2011)
  • Author(s): Ishiura H, et al
  • Organizer: 第34回神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-16
• [Presentation] 遺伝性神経疾患の研究 (2011)
  • Author(s): 石浦浩之, ら
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋(招待講演)
  • Year and Date: 2011-05-20
• [Presentation] 大規模シーケンスによるposterior column ataxia with retinitis pigmentosaの原因遺伝子探索 (2011)
  • Author(s): 石浦浩之, ら
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] Clinical characteristics of an oculopharynge al myopathy family linked to a novel locus (2011)
  • Author(s): Ishiura H, et al
  • Organizer: 64^<th> Annual Meeting of American Academy of Neurology
  • Place of Presentation: ハワイ、アメリカ
  • Year and Date: 2011-04-14
• [Presentation] Siblings of pathologically proven multiple system atrophy : an application of whole genome analysis toward finding strong genetic factors for sporadic diseases. (2010)
  • Author(s): Ishiura H, et al.
  • Organizer: Annual meeting of American Society of Human Genetics
  • Place of Presentation: ワシントン(アメリカ)
  • Year and Date: 2010-11-03
• [Presentation] Massively parallel sequence analysis for revealing causes of neur omuscular disorders. (2010)
  • Author(s): 石浦, ら
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-21
• [Presentation] SNPアレイを用いたハイスループット連鎖解析システムの診療への応用 (2010)
  • Author(s): 石浦, ら
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-20
• [Presentation] Application of a microarray-based whole mitochondrial DNA sequence analys is for molecular diagnosis of mitochondrial diseases. (2010)
  • Author(s): Ishiura H, et al.
  • Organizer: Annual meeting of American Academy of Neurology
  • Place of Presentation: トロント(カナダ)
  • Year and Date: 2010-04-14