Analysis for the molecular mechanism of Inheited GPI Deficiency

• Project/Area Number: 23590363
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Osaka University
• Principal Investigator: MURAKAMI Yoshiko 大阪大学, 微生物病研究所, 准教授 (00304048)
• Co-Investigator(Renkei-kenkyūsha): 木下 タロウ 大阪大学, 微生物病研究所, 教授 (10153165)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 先天性GPI欠損症 / てんかん / 精神運動発達障害 / 高アルカリフォスファターゼ血症 / 発作性夜間ヘモグロビン尿症 / 高アルカリホスファターゼ血症 / 補体制御因子 / 溶血性貧血 / 深部静脈血栓症 / 精神発達遅滞 / GPIアンカー型蛋白質 / GPIアンカー

Research Abstract

Glycosylphosphatidylinositol (GPI) is a glycolipid, which anchors 150 proteins to the cell surface. There are at least 27 genes involved in the biosynthesis and transport of GPI-anchored proteins (GPI-APs). Many inherited GPI deficiencies (IGDs) have been found using whole-exome sequencing. Patients with IGD have only a partial deficiency because complete GPI deficiency causes embryonic death. The major symptoms of IGDs include intellctual disability, epilepsy, and multiple organ anomalies. These symptoms vary in severity depending upon the degree of the defect and/or position in the pathway of the affected gene. Hyperphosphatasia is observed in some patients with IGDs. The possibility of IGD should be considered in patients with seizures and intellctual disability. The presence of hyperphosphatasia is strong evidence of IGD. Flow cytometric analysis of GPI-APs on granulocytes is useful for the detection of IGD. It should be noted that Vitamin B6 is sometimes effective for seizures.

Research Products

• [Journal Article] Mutations in PGAP3 impair GPI-anchor maturation and lead to intellectual disability with hyperphosphatasia and additional phenotypic features. (2014)
  • Author(s): Howard MF* Murakami Y* Pagnamenta AT, Haas CD, Fischer B, Hecht J, Keays DA, Knight SJL, Kolsch U, Kruger U, Leiz S, Maeda Y, Mitchell D, Mundlos S, Philipps JA, Robinson PN, Kini U, Taylor JC, Horn D, Kinoshita T, and Krawitz PM. （*equally contribution)
  • Journal Title: Am J Hum Genet Volume: 94 Issue: 2 Pages: 278-287
  • DOI: 10.1016/j.ajhg.2013.12.012
  • Peer Reviewed
• [Journal Article] Glycosylphosphatidylinositol (GPI) anchor deficiency caused by mutations in PIGW is associated with West syndrome and hyperphosphatasia with mental retardation syndrome. (2014)
  • Author(s): Chiyonobu T, Inoue N, Morimoto M, Kinoshita T, and Murakami Y.
  • Journal Title: J Med Genet. Volume: 51 Issue: 3 Pages: 203-207
  • DOI: 10.1136/jmedgenet-2013-102156
  • Peer Reviewed
• [Journal Article] Case report with vitamin B6 responsive epilepsy due to inherited GPI deficiency. (2013)
  • Author(s): Kuki, I., Y. Takahashi, Okazaki, Ebara, N. Inoue, T. Kinoshita and Y. Murakami.
  • Journal Title: Neurology Volume: 81 Issue: 16 Pages: 1467-1469
  • DOI: 10.1212/wnl.0b013e3182a8411a
  • Peer Reviewed
• [Journal Article] A case of paroxysmal nocturnal hemoglobinuria (PNH) caused by a germline mutation and a somatic mutation in PIGT (2013)
  • Author(s): Krawitz, P. M., B. Hochsmann, Y. Murakami, B. Teubner, U. Kruger, E. Klopocki, H. Neitzel, A. Hollein, D. Parkhomchuk, J. Hecht, P. N. Robinson, S. Mundlos, T. Kinoshita and H. Schrezenmeier
  • Journal Title: Blood Volume: 122 Issue: 7 Pages: 1312-1315
  • DOI: 10.1182/blood-2013-01-481499
  • Peer Reviewed
• [Journal Article] PGAP2 Mutations, Affecting the GPI-Anchor-Synthesis Pathway, Cause Hyperphosphatasia with Mental Retardation Syndrome (2013)
  • Author(s): Krawitz, P. M. Murakami, Y. Riess, A. Hietala, M. Kruger, U. Zhu, N. Kinoshita, T. Mundlos, S. Hecht, J. Robinson, P. N. Horn, D.
  • Journal Title: Am J Hum Genet Volume: 92(4) Issue: 4 Pages: 584-589
  • DOI: 10.1016/j.ajhg.2013.03.011
  • Peer Reviewed
• [Journal Article] Hypomorphic Mutations in PGAP2, Encoding a GPI-Anchor-Remodeling Protein, Cause Autosomal-Recessive Intellectual Disability (2013)
  • Author(s): Hansen, L. Tawamie, H. Murakami, Y. Mang, Y. Ur Rehman, S. Buchert, R. Schaffer, S. Muhammad, S. Bak, M. Nothen, M. M. Bennett, E. P. Maeda, Y. Aigner, M. Reis, A. Kinoshita, T. et al.
  • Journal Title: Am J Hum Genet Volume: 92(4) Issue: 4 Pages: 575-583
  • DOI: 10.1016/j.ajhg.2013.03.008
  • Peer Reviewed
• [Journal Article] Occupancy of whole blood cells by a single PIGA-mutant clone with HMGA2 amplification in a paroxysmal nocturnal haemoglobinuria patient having blood cells with NKG2D ligands (2013)
  • Author(s): Hanaoka, N., Y. Murakami, M. Nagata, K. Horikawa, S. Nagakura, Y. Yonemura, S. Murata, T. Sonoki, T. Kinoshita, H. Nakakuma
  • Journal Title: Br. J. Haematol. Volume: 160 Issue: 1 Pages: 114-116
  • DOI: 10.1111/bjh.12093
  • Peer Reviewed
• [Journal Article] Mutations in PIGO, a member of the GPI anchor synthesis pathway, cause hyperphosphatasia with mental retardation (2012)
  • Author(s): Krawitz, P. M., Y. Murakami, J. Hecht, U. Kruger, S. E. Holder, G. R. Mortier, B. delle Chiaie, M. D. Thompson, T. Roscioli, S. Kielbasa, T. Kinoshita, S. Mundlos, P. N. Robinson and D. Horn
  • Journal Title: Am. J. Hum. Genet Volume: 91 Issue: 1 Pages: 146-151
  • DOI: 10.1016/j.ajhg.2012.05.004
  • Peer Reviewed
• [Journal Article] Persistently high quality of life conferred by coexisting congenital deficiency of terminal complement C9 in a paroxysmal nocturnal hemoglobinuria patient. (2012)
  • Author(s): Hanaoka N, Murakami Y, Nagata M, Nagakura S, Yonemura Y, Sonoki T, Kinoshita T, Nakakuma H.
  • Journal Title: Blood Volume: 119(16) Issue: 16 Pages: 3866-3868
  • DOI: 10.1182/blood-2012-02-408161
  • Peer Reviewed
• [Journal Article] Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia-mental retardation syndrome (2012)
  • Author(s): Murakami, Y., N. Kanzawa, K. Saito, P. M. Krawitz, S. Mundlos, P. N. Robinson, A. Karadimitris, Y. Maeda and T. Kinoshita
  • Journal Title: J. Biol. Chem Volume: 287 Issue: 9 Pages: 6318-6325
  • DOI: 10.1074/jbc.m111.331090
  • Peer Reviewed
• [Journal Article] Deregulated expression of HMGA2 is implicated in clonal expansion of PIGA deficient cells in paroxysmal nocturnal haemoglobinuria (2012)
  • Author(s): Murakami, Y., N. Inoue, T. Shichishima, R. Ohta, H. Noji, Y. Maeda, J. Nishimura, Y. Kanakura and T. Kinoshita
  • Journal Title: Br. J. Haematol Volume: 156 Issue: 3 Pages: 383-387
  • DOI: 10.1111/j.1365-2141.2011.08914.x
  • Peer Reviewed
• [Journal Article] Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome. (2012)
  • Author(s): Murakami Y, Kanzawa N, Saito K, Krawitz PM, Mundlos S, Robinson PN, Karadimitris A, Maeda Y, Kinoshita T.
  • Journal Title: J Biol Chem. Volume: 287 Pages: 6318-6325
  • Peer Reviewed
• [Journal Article] Deregulated expression of HMGA2 is implicated in clonal expansion of PIGA deficient cells in paroxysmal nocturnal haemoglobinuria. (2012)
  • Author(s): Murakami Y, Inoue N, Shichishima T, Ohta R, Noji H, Maeda Y, Nishimura J, Kanakura Y, Kinoshita T.
  • Journal Title: Br J Haematol. Volume: 156 Pages: 383-387
  • Peer Reviewed
• [Presentation] Inherited GPI-anchor deficiencies caused by the hypomorphic mutations in PIGA gene: comparison to paroxysmal nocturnal hemogrobinuria (2013)
  • Author(s): Yoshiko Murakami, Mitsuhiro Kato, Hirotomo Saitsu, Kenjiro Kikuchi, Shuei, Watanabe, Mizue Iai, Ryuki Matsuura, Rumiko Takayama, Chihiro Ohba, Shin-ichiro Hamano, Hitoshi Osaka, Kiyoshi Hayasaka, Naomichi Matsumoto, Taroh Kinoshita
  • Organizer: 55^<th> ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, LA USA
  • Year and Date: 2013-12-09
• [Presentation] Inherent resistance to eculizumab in PNH (2013)
  • Author(s): Masaki Yamamoto, Jun-ichi Nishimura, Shin Hayashi, Kazuma Ohyashiki, Kiyoshi Ando, Hedeyuki Noji, Kunio Kitamura, Tetsuya Eto, Toshihiko Ando, Masayuki Masuko, Tutomu Shichishima, Hirohiko Shibayama, Masakazu Hase, Johji Inazawa, Taroh Kinoshita, Yuzuru Kanakura
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-11
• [Presentation] 先天性GPI欠損症——発達障害・てんかんを主症状とする新たな疾患—— (2013)
  • Author(s): 村上良子
  • Organizer: 第7回南大阪遺伝診療研究会
  • Place of Presentation: 堺市
  • Year and Date: 2013-09-27
• [Presentation] GPIアンカー生合成に関与する遺伝子群の解析 (2013)
  • Author(s): 藤田盛久, 中村昇太, 平田哲也, 村上良子, 前田裕輔, 木下タロウ
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜市
  • Year and Date: 2013-09-12
• [Presentation] 精神発達遅滞・てんかんを主症状とする疾患 (2013)
  • Author(s): 村上良子, 井上徳光, 九鬼一郎, 高橋幸利, 木下タロウ
  • Organizer: 第50回補体シンポジウム
  • Place of Presentation: 旭川市
  • Year and Date: 2013-07-06
• [Presentation] 精神発達遅延・てんかんを主症状とする疾患:先天性GPI欠損症の疾患概念の確立に向けて (2013)
  • Author(s): 村上良子, 井上徳光, 九鬼一郎, 高橋幸利, 木下タロウ
  • Organizer: 第55回日本小児神経学会学術集会
  • Place of Presentation: 大分市
  • Year and Date: 2013-05-31
• [Presentation] 高アルカリフォスファターゼ血症を呈する先天性GPI欠損症–肢根型点状軟骨異形成症との関連についての最近の知見も含めて (2013)
  • Author(s): 村上良子
  • Organizer: 第17回大阪小児骨系統疾患研究会
  • Place of Presentation: 大阪市
  • Year and Date: 2013-02-16
• [Presentation] 精神発達遅延・てんかんを主症状とする疾患：先天性GPI欠損症の疾患概念の確立に向けて (2013)
  • Author(s): 村上良子、井上徳光、九鬼一郎、高橋幸利、木下タロウ
  • Organizer: 第55回日本小児神経学会学術集会
  • Place of Presentation: 大分市
• [Presentation] 精神発達遅滞・てんかんを主症状とする疾患 (2013)
  • Author(s): 村上良子、 井上徳光、 九鬼一郎、 高橋幸利、木下タロウ
  • Organizer: 第50回補体シンポジウム
  • Place of Presentation: 旭川医科大学
• [Presentation] GPIアンカー生合成に関与する遺伝子群の解析 (2013)
  • Author(s): 藤田盛久、中村昇太、平田哲也、村上良子、前田裕輔、木下タロウ
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] 先天性GPI欠損症―発達障害・てんかんを主症状とする新たな疾患― (2013)
  • Author(s): 村上良子
  • Organizer: 第7回南大阪遺伝診療研究会
  • Place of Presentation: ホテル・アゴーラリージェンシー堺
  • Invited
• [Presentation] nherent resistance to eculizumab in PNH (2013)
  • Author(s): Masaki Yamamoto, Jun-ichi Nishimura, Shin Hayashi, Kazuma Ohyashiki, Kiyoshi Ando, Hedeyuki Noji, Kunio Kitamura, Tetsuya Eto, Toshihiko Ando, Masayuki Masuko, Tutomu Shichishima, Hirohiko Shibayama, Masakazu Hase, Johji Inazawa, Taroh Kinoshita, Yuzuru Kanakura,
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌
  • Invited
• [Presentation] Inherited GPI-anchor deficiencies caused by the hypomorphic mutations in PIGA gene: comparison to paroxysmal nocturnal hemogrobinuria (2013)
  • Author(s): Yoshiko Murakami, Mitsuhiro Kato, Hirotomo Saitsu, Kenjiro Kikuchi, Shuei, Watanabe, Mizue Iai, Ryuki Matsuura, Rumiko Takayama, Chihiro Ohba, Shin-ichiro Hamano, Hitoshi Osaka, Kiyoshi Hayasaka, Naomichi Matsumoto, Taroh Kinoshita,
  • Organizer: 55th ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, LA USA.
  • Invited
• [Presentation] 先天性GPI欠損症-疾患概念の確率に向けて—Screening patients with inhierited GPI anchor deficiency to establish cincept of the new disease (2012)
  • Author(s): 村上良子, 井上徳光, 高橋幸利, 木下タロウ
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡市
  • Year and Date: 2012-12-12
• [Presentation] Screening patients with inherited GPI anchor deficiency to establish concept of the new disease (2012)
  • Author(s): Yoshiko Murakami, Norimitsu Inoue, Yusuke Maeda, Yukitoshi Takahashi, Taroh Kinoshita
  • Organizer: XXIV International Complement Workshop
  • Place of Presentation: クレタ島ギリシャ
  • Year and Date: 2012-10-12
• [Presentation] 先天性GPI欠損症てんかん・発達障害を主症状とする新たな疾患 (2012)
  • Author(s): 村上良子
  • Organizer: 関西ディスモルフォロジー研究会
  • Place of Presentation: 大阪市
  • Year and Date: 2012-09-01
• [Presentation] 先天性GPI欠損症—てんかん・発達障害を主症状とする新たな疾患概念の確立 (2012)
  • Author(s): 村上良子
  • Organizer: 第78回大阪小児神経懇話会
  • Place of Presentation: 大阪市
  • Year and Date: 2012-06-28
• [Presentation] Screening patients with inherited GPI anchor deficiency to establish concept of the new disease (2012)
  • Author(s): Yoshiko Murakami, Norimitsu Inoue, Yusuke Maeda, Yukitoshi Takahashi and Taroh Kinoshita
  • Organizer: XXIV International Complement Workshop
  • Place of Presentation: Chania, Greece
• [Presentation] 発作性夜間血色素尿症におけるGPI欠損細胞の拡大機序について (2012)
  • Author(s): 村上良子、井上徳光、金倉譲、西村純一、木下タロウ
  • Organizer: 第49回補体シンポジウム
  • Place of Presentation: 大阪
• [Presentation] 先天性GPI欠損症 -疾患概念の確立に向けて- (2012)
  • Author(s): 村上良子、井上徳光、高橋幸利、木下タロウ
  • Organizer: 第３５回分子生物学会
  • Place of Presentation: 福岡
• [Presentation] 補体研究:基礎から臨床へ発作性夜間血色素尿症をはじめとするGPI欠損症について (2011)
  • Author(s): 村上良子, 井上徳光, 七島勉, 太田里永子, 野地秀義, 前田裕輔, 西村純一, 木下タロウ
  • Organizer: 第48回補体シンポジウム
  • Place of Presentation: 名古屋市(特別企画シンポジウム)
  • Year and Date: 2011-09-02
• [Presentation] Release of alkaline phosphatase caused by PIGV mutations in patients with Hyperphosphatasia-Mental Retardation syndrome (HPMR), a recently found second inherited GPI anchor deficiency (2011)
  • Author(s): Yoshiko Murakami, Peter M. Krawitz, Peter N. Robinson, Stefan Mundlos, Noriyuki Kanzawa, Yusuke Maeda, Taroh Kinoshita
  • Organizer: Glyco 21 (21th International Symposium on Glyconjugates)
  • Place of Presentation: ウィーン, オーストリア
  • Year and Date: 2011-08-22
• [Presentation] Release of alkaline phosphatase caused by PIGVmutations in patients with Hyperphosphatasia-Mental Retardation syndrome (HPMR), recently found second inherited GPI anchor deficiency. (2011)
  • Author(s): Murakami,Y., Krawitz, PM., Robinson, PN, Mundlos, S., Maeda Y., and Kinoshita,T.
  • Organizer: Glyco 21
  • Place of Presentation: ウィーン
• [Presentation] 発作性夜間血色素尿症をはじめとするGPI欠損症について (2011)
  • Author(s): 村上良子、太田里永子、井上徳光、木下タロウ
  • Organizer: 第４８回補体シンポジウム「補体研究：基礎から臨床へ」(招待講演)
  • Place of Presentation: 名古屋
• [Presentation] 先天性GPI欠損症―てんかん・発達障害を主症状とする新たな疾患概念の確立―
  • Author(s): 村上良子
  • Organizer: 第７８回大阪小児神経懇話会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] 先天性GPI欠損症ｰてんかん・発達障害を主症状とする新たな疾患-
  • Author(s): 村上良子
  • Organizer: 第６０回関西ディスモルフォロジー研究会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] 先天性GPI欠損症―てんかん・発達障害を主症状とする新たな疾患概念の確立―
  • Author(s): 村上良子
  • Organizer: 第１７回大阪小児骨系統疾患研究会
  • Place of Presentation: 大阪
  • Invited
• [Remarks]
  • URL: http://www.biken.osaka-u.ac.jp/biken/men-eki-huzen/index.html