Molecular genetical approach for multifactorial neuropsychiatric diseases

• Project/Area Number: 16390326
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Kagoshima University
• Principal Investigator: SANO Akira Kagoshima University, Graduate School of Medical and Dental Sciences, Professor, 大学院・医歯学総合研究科, 教授 (30178800)
• Co-Investigator(Kenkyū-buntansha): NAKAMURA Masayuki Kagoshima University, University Hospital Faculty of Medicine and Dentistry, Research Associate, 医学部・歯学部附属病院, 助手 (90332832)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥11,700,000 (Direct Cost: ¥11,700,000); Fiscal Year 2005: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2004: ¥8,100,000 (Direct Cost: ¥8,100,000)
• Keywords: Chorea-acanthocytosis / CHAC (VPS13A) / model mouse / phenotype / C57BL / 6J / BALB / cbyJ / DBA / 2J / modifying genes / 神経変性 / 個体差 / 多因子 / modifier遺伝子 / 運動障害 / 有棘赤血球症 / CHAC

Research Abstract

Chorea-acanthocytosis (ChAc) is a human hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of striatum has been reported in brain pathology. Clinically, ChAc shows Huntington's disease-like neuropsychiatric symptoms and red blood cell acanthocytosis, and much variation in symptoms are observed even in brother cases. Recently, we identified the gene, CHAC (VPS13A) encoding a protein named chorein in which a deletion mutation was found in Japanese ChAc families. Then we identified the mouse CHAC cDNA sequence and the exon-intron structures of the gene, and produced a ChAc-model mouse introducing #60-61 exons-deletion corresponding to a human disease mutation by gene-targeting technique. The mice began to show acanthocytosis and motor disturbance after becoming old age. In behavioral observations, locomotor activity was significantly decreased, and the contact time at social interaction test was decreased significantly in the model mice. In the brain pathology, many apoptotic cells were observed in the striatum of the mutant mice. In neurochemical determination, dopamine-metabolite, HVA concentration decreased significantly in the portion including midbrain of the mutant mice. These findings are well consistent with the human results reported elsewhere and indicate that the ChAc-model mice showed mild phenotype with late adult onset. The ChAc-model mouse therefore provides a good model system to study the human disease. The mice are produced as hybrid of 129 and C57BI/B6, and there are much variations in the degree of degeneration in the sriatum and other phenotypes, which might suggest the existence of modifier genes. Then we produced the ChAc-model mouse with three kinds of strains-background, C57BL/6J, BALB/cbyJ, and DBA/2J. Only DBA/2J ChAc-model mice showed reduced body weight from 3 months after birth.

Research Products

• [Journal Article] A gene-targeted mouse model for chorea-acanthocytosis (2005)
  • Author(s): Y.Tomemori, M.Ichiba, A.Kusumoto, E.Mizuno, D.Sato, S.Muroya, M.Nakamura, H.Kawaguchi, H.Yoshida, S.Ueno, K.Nakao, K.Nakamura, A.Aiba, M.Katsuki, A.Sano
  • Journal Title: J. Neurochem. 92・4 Pages: 759-766
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] セロトニントランスポーター (2005)
  • Author(s): 中村雅之, 佐野輝
  • Journal Title: 分子精神医学 5・2 Pages: 72-74
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 精神疾患の遺伝子研究 (2005)
  • Author(s): 中村雅之, 佐野輝
  • Journal Title: 精神医学 47・4 Pages: 348-358
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 分子精神医学 (2005)
  • Author(s): 佐野輝
  • Journal Title: 九州神経精神医学 51・2 Pages: 107-112
  • NAID: 40006925621
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 結合失調症 (2005)
  • Author(s): 中村雅之, 佐野輝
  • Journal Title: 分子細胞治療 4 Pages: 60-66
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A gene-targeted mouse model for chorea-acanthocytosis. (2005)
  • Author(s): Y.Tomemori, M.Ichiba, A.Kusumoto, E.Mizuno, D.Sato, S.Muroya, M.Nakamura, H.Kawaguchi, H.Yoshida, S.Ueno, K., Nakao, K.Nakamura, A.Aiba, M.Katsuki, A.Sano
  • Journal Title: J.Neurochem. 92・4 Pages: 759-766
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A gene-targeted mouse model for chorea-acanthocytosis (2005)
  • Author(s): Y.Tomemori, M.Ichiba, A.Kusumoto, E.Mizuno, D.Sato, S.Muroya, M.Nakamura, H.Kawaguchi, H.Yoshida, S.Ueno, K.Nakao, K.Nakamura, A.Aiba, M.Katsuki, A.Sano
  • Journal Title: J. Neurochem 92・4 Pages: 759-766
• [Journal Article] Changes in Expression of Prosaposin in the Rat Facial Nerve Nucleus after Facial Nerve Transection (2005)
  • Author(s): K.Unuma, J.Chen, S.Saito, N.Kobayashi, K.Sato, K.Saito, H.Wakisaka, K.Mominoki, A.Sano, S.Matsuda
  • Journal Title: Neurosci. Res. 52・3 Pages: 220-227
  • NAID: 10016476820
• [Journal Article] A gene-targeted mouse model for chorea-acanthocytosis (2005)
  • Author(s): Y.Tomemori, et al.
  • Journal Title: J.Neurochem. 92 Pages: 759-766
• [Journal Article] 精神神経疾患の遺伝学-臨床遺伝学から分子遺伝学- (2004)
  • Author(s): 佐野輝
  • Journal Title: 精神神経学雑誌 106・12 Pages: 1604-1609
  • NAID: 10018962458
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 有棘赤血球舞踏症の分子遺伝学 (2004)
  • Author(s): 佐野輝
  • Journal Title: Current Insights in Neurological Science 12 Pages: 2-4
• [Journal Article] 精神神経疾患の遺伝学-臨床遺伝学から分子遺伝学 (2004)
  • Author(s): 佐野輝
  • Journal Title: 精神神経学雑誌 106 Pages: 1604-1609
  • NAID: 10018962458
• [Journal Article] Association of AKT1 Haplotypes with the Risk of Schizophrenia in Iranian Population
  • Author(s): S.N.Bajestan, A.H.Sabouri, M.Nakamura, H.Takashima, M.R.Keikhaee, F.Behdani, Mohammad, R.F., M.R.Sargolzaee, M.N.Bajestan, Z.Sabouri, Es.Khayami, S.Haghighi, S.B.Hashemi, N.Eiraku, H.Tufani, H.Najmabadi, K.Arimura, A.Sano, M.Osame
  • Journal Title: Am J. Med Genet (in press)
• [Book] Neuroacanthocytosis Syndromes(分担執筆pp.39-44、Choreaacanthocytosis with the Ehime-deletion mutation) (2004)
  • Author(s): S.Ueno et al.
  • Total Pages: 288
  • Publisher: Springer, Berlin, Germany (A.Danek eds.)