単一遺伝子病の分子・細胞生物学的研究,疾患発症の分子機構の解明

1991 Fiscal Year Annual Research Report

• Project/Area Number: 03265102
• Research Institution: Kumamoto University
• Principal Investigator: 松田 一郎 熊本大学, 医学部, 教授 (10000986)
• Co-Investigator(Kenkyū-buntansha): 岡田 伸太郎 大阪大学, 医学部, 教授 (30028609) ; 折居 忠夫 岐阜大学, 医学部, 教授 (20045339) ; 北川 照男 日本大学, 医学部, 教授 (50058765) ; 成澤 邦明 東北大学, 医学部, 教授 (90004647) ; 山村 研一 熊本大学, 医学部, 教授 (90115197)
• Keywords: 先天代謝異常 / 遺伝子解析 / モデル動物 / レセプタ-異常 / 細胞小器官異常 / 遺伝子導入 / 遺伝子発現

Research Abstract

単一遺伝子病の分子・細胞生物学的研究,疾患発症の分子機構の解明は以下の如く、いくつかのプロジェクトに分かれ、班員9人,公募研究員12人により行われた。
(1)先天性酵素異常症の変異遺伝子の解明:対象となった疾患は、Gancher病,TayーSachs病,βガラクトシダ-ゼ欠損症,中鎖アシルCoAデヒドロゲナ-ゼ欠損症,チロシナ-ゼ欠損症,オルニチントランスカルバミラ-ゼ欠損症,アルギナ-ゼ欠損症,チロジン血症III型,NADHシトクロ-ムb_5還元酵素異常症などで、それぞれについて変異遺伝子の解明がなされた。一部の変異遺伝子については培養細胞を用いた発現実験も行われた。 (2)モデル動物を用いた病態解明:クラベ病モデルマウス,ニ-マンピックマウスを用いて病態解明がなされた。いずれも将来の変異遺伝子解明を目指し、責任遺伝子の単離が行われた。 (3)レセプタ-,転送系タンパク質,血清タンパク質異常症の分子病理:インスリンレセプタ-,グルコ-ストランスホ-タ-,b型シトクロム(慢性肉芽腫症で欠損),プロテインS,アポリポプロテインなどの欠損症について遺伝子レベルでの解明が進められた。一部のタンパク(PC)は、変異のために、細胞内転送・分泌にも障害が生ずることが示された。 (4)細胞小器官異常の分子病理:ミトコンドリア脳筋症,ペルオキシゾ-ム異常(Zellweger症候群)につてい研究され、それぞれの変異遺伝子が世界に先駆けて解明された。 (5)新しい展望に立つ研究:動物個体レベル・細胞レベルで、遺伝子相同組み換えなどを用いた遺伝子導入の研究や、組織特異的な遺伝子発現についての研究がなされた。いずれも新しい展開を目指した研究で、将来の遺伝病研究に寄与するところが大である。

Research Products

• [Publications] Ichiro Matsuda: "Four novel gne mutations in six Japanese male patients with neonatal or late onset OTC deficiency." 発表予定.
• [Publications] Uchino Takako: "Three novel mutations in the liverーtype arginase gene in three unrelated Japanese patients with argininemia." 発表予定.
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• [Publications] 松浦 稔展: "オルニチントランスカルバミラ-ゼ欠損症の遺伝子診断の現状" 小児科内科. 23. 1695-1698 (1991)
• [Publications] Matsuda Ichiro: "Retrospective survey of urea cycle disorders : Part 1. clinical and laboratory observation of thirtyーtwo Japanese male patients with ornithine transcarbamylase deficiency." Am.J.Med.Genet. 38. 85-89 (1991)
• [Publications] Nagata Noriyuki: "Retrospective survey of urea cycle disorders : Part 2. Neurological outcome in fortyーnine Japanese patients with urea cycle enzymopathies." Am.J.Med.Genet.40. 477-481 (1991)
• [Publications] Halt Akira: "A Novel missense mutation in exon 8 of the ornithine transcarbamylase gene in two unrelated male patients with mild ornithine transcarbamylase deficiency." Hum.Genet.87. 28-32 (1991)
• [Publications] Era T.: "Differentiation of growth signal requirement of B lymphocyte precursoris directed by expression of immunoglobulin." Embo J.10. 337-342 (1991)
• [Publications] Yamada G.: "Specific depletion of the B cell population induced by aberrant expression of human IRF‐1 (interferon regulatory factor‐1) gene in transgenic mice." Proc.Natl.Aad.Sci.USA.88. 532-536 (1991)
• [Publications] Shimada T.: "correction of ornithine transcarbamulase(OTC)deficiency in spfーash mice by introduction of rat OTC gene." FEBS lett.279. 198-200 (1991)
• [Publications] Yi S.: "Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene : Pathological similarity to human familial amyloidotic polyneuropathy, type 1." Amer.J.Pathol.138. 403-412 (1991)
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• [Publications] Meneta T.: "(BALB/cx C57BL/6)F1 mice are tolerant to undetectable mixed haplotype Aβ^dAa^d and mixed isotype Aβ^dEa^d self class 〓 molecules." Int.immurol.3. 453-460 (1991)
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• [Publications] Tashiro F.: "Role of serum amyloid P component for systemic amyloidosis in transgenic mice carying human mutant transthretin gene." Gerontology. 37. 56-62 (1991)
• [Publications] Araki K.: "Development of two types of hepatocellular carcinoma in transgenic mice carrying SV40 large T‐antigen gene." Carcinogenesis. 12. 2059-2062 (1991)
• [Publications] Uno M.: "Complete preventionof diabetes in transgenic NOD mice expressing I‐E molecules." Immunol.Letters. 31. 47-52 (1991)
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• [Publications] Kure S.: "Structural and expression analysis of normal and mutant mRNA encoding glycine decarboxylase : Three bse deletion in mRNA causes nonketotic hyperglycinemia." Biochem.Biophs.Res.Comun.174. 1170-1182 (1991)
• [Publications] Matsubasa Y.: "Prevalence of K329E mutation in medium chain acylーCoA dehydrogenase gene determined from Guthrie cards." LANCET. 338. 552-553 (1991)
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• [Publications] Eto Y.: "The role of proteases and lipids in neuronal ceriod lipofuscinosis(NCL)." Amer.J.Med Genetics.(1992)
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• [Publications] Yajima Shigehiro: "complementation study of peroxisomeーdeficient disorders by immunofluorescence staining and characterization of fused cells." Hum.Genet.
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• [Publications] Sukegawa Kazuko: "Intermediate form of mcopolysaccharidosis typeII (Hunter disease) : A C^<1327>to T substitution in the iduronate sulfatase." Biochem.Biophys.Res.Comm.(1992)
• [Publications] Fukao Toshiyuki: "Identification of three mutant alleles of the gene for mitochondrial acetoacetyl CoA thiolase : a complete analysis of two generations of a family with 3ーketothiolase deficiency" J.Clin.Invest.(1992)
• [Publications] Wajner Moacir: "Biochemical investigation of a Brazilian patient with a defect in mitochondrial acetoacetylーcoenzyme Athiolase." Clin.Genet.(1992)
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• [Publications] 岡田 伸太郎: "ヒスチジン血症" 今日の小児治療指針第9班. 263 (1991)
• [Publications] 岡田 伸太郎: "特集・臨床医学の展望ー先天性代謝異常" 日本医事新報. 3485. 43-48 (1991)
• [Publications] 乾 幸治: "糖原病に伴うミオパチ-" 小児内科. 23(7). 1068-1072 (1991)
• [Publications] Nishimoto J.: "Expression of the β ーhexos aminidase a subunit gene with the fourーinsertion of infantile jewish tayーsachs disease." J.biological Chemistry. 266. 14306-14309 (1991)
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• [Publications] Tsukuda K.: "Peptideーbased radioimmunoassay specific for GLUT1 glucose transporter." Diabetes. 40. 315-318 (1991)
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• [Publications] Lin JーL.: "Altered expression of glucose transporter isoforms with aging in ratsーSelective decrease in GluT4 in the fat tissue and skeletal muscle." Diabetologia. 34. 477-482 (1991)
• [Publications] Asano T.: "Expression of the GLUT1 glucose transporter increases thymidine uptake in CHO cells at low glusose concentrations." Cancer Res.51. 4450-4454 (1991)
• [Publications] Asano T.: "The role of Nーglycosylation of GLUT1 for glucose transport activity." J.Biol.Chem.266. 24632-24636 (1991)
• [Publications] Asano T.: "UPーregulation of GLUT2 mRNA by glucose,mennose,and fructose in isolated rat hepatocytes." Diabetes. 41. 22-25 (1992)
• [Publications] Shibasaki Y.: "Two glucose transporter isoforms are sorted differentiall and are expressed in distinct cellular compartments." Biochem.J.281. 829-834 (1992)
• [Publications] Ohuchi K.: "A transgenic mouse line developed to express human amyloidogenic transthyretin cDNA in the brain." Biochem.Internat.23. 809-817 (1991)
• [Publications] Murakami T.: "An attempt to study the role of serum amyloid P component in the formation of amyloid deposits in a transgenic mouse model of familial amyloidotic polyneuropathy in “Amyloid and Amyloidosis 1990",eds." J.B.Natvig et al.Kluwer avademic Publishers,Dordrecht. 276-279 (1991)
• [Publications] Tashiro F.: "Role of serum amyloid P component for systemic amyloidosis in transgenic mice carrying human mutant transthyretin" Gerontology. 37. 56-62 (1991)