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

1993 Fiscal Year Annual Research Report

• Project/Area Number: 04260102
• Research Institution: Kumamoto University
• Principal Investigator: 松田 一郎 熊本大学, 医学部, 教授 (10000986)
• Co-Investigator(Kenkyū-buntansha): 衛藤 義勝 東京慈恵会医科大学, 医学部, 助教授 (50056909) ; 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)
• Keywords: 先天代謝異常 / 遺伝子解析 / モデル動物 / レセプター異常 / 細胞小器官異常 / 遺伝子導入 / 遺伝子発現

Research Abstract

1.新しい遺伝子の単離・同定とその変異解析
ホロカルボキシラーゼ合成酵素(成沢)、ガラクトセレブロシダーゼ、クラベ病病因酵素(岡田)、フマリルアセト酢酸分解酵素、高チロジン血症I型病因酵素(松田)、betaヒドロキシフェニルピルビン酸酸化酵素、高チロジン血症III型病因酵素(松田)などの遺伝子が世界に先駆けて単離・同定された。ホモカルボキシラーゼ合成酵素欠損症、高チロジン血症I型については変異遺伝子が同定された。また高チロジン血症III型についてはモデル動物でexon 7のスキップが見出された。ムコ多糖体症(折居)のII,IVA,VIIの各型についての責任遺伝子の単離・同定、さらに変異遺伝子の解析が行われた。いずれも世界最初である、IVA型の変異遺伝子の中には日本人、欧米人に共通してdouble gene deletionがあることを見い出した。
2.新しい酵素異常症の責任遺伝子の単離・同定
極長鎖アシルCoAデヒドロゲナーゼ欠損症を、11例の患者で確認し、さらにその責任遺伝子、変異遺伝子を単離・同定した(橋本)。
3.遺伝子治療を目標とした基礎研究
Gaucher病、metachromatic leukodystrophyの変異遺伝子解析を日本人患者について行い、それぞれ60%,50%に特定の変異遺伝子が見出された。さらに、マウス骨髄細胞を目標細胞に選びそれぞれの遺伝子(cDNA)をレトロウイルスベクターを用いて遺伝子導入を試み、成功した。
4.糖尿病の遺伝子解析
ミトコンドリア遺伝子tRNA^<LEU(UUR)>の3243A→Gの変異について、母子共にIDDMの300家系をスクリーニングし、4家系にそれをみつけた。またslowly progressive IDDMの患者27名中3名にも同じ変異遺伝子をみつけた(岡)。NIDDMの患者について、グリコーゲン合成酵素遺伝子多型を解析し、一部の患者で特定の遺伝子多型との間に有意の相関を見出した(北川)。
5.トランスジェニックマウスを用いた研究
疾患モデル動物の作製に際して、遺伝子の相関組み換え率を高めるため、ベクターの安定性について検討した(島田)、その結果、3′末端部位を修飾することで、その目的を達することができることが判明した。
6.哺乳類発生異常の遺伝解析
マウスMHCのK領域の近くに胎生致死をおこすt^<w5>変異が存在することも見出し、その変異遺伝子の単離同定を試みた(阿部)。また同定に成功していないが、有力な候補者を見出し研究を続けている。

Research Products

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