熱ショックタンパク60に点変異を持つゼブラフィッシュ変異個体が成長後に突然死して, 野生型個体と比較して寿命が短いことを発見した。原因遺伝子不明の拡張型心筋症家系において熱ショックタンパク60の異常をスクリーニングしたところ, 点変異を持つ一家系を発見した。熱ショックタンパク60に点変異を持つゼブラフィッシュ個体に温度や低酸素のストレスを加えると房室ブロックを高頻度に発症して心不全になることを発見した。
This study is aimed to determine if hsp60 dysfunction leads to cardiomyopathy. We have developed a zebrafish mutant, nbl, which has a missense mutation in hsp60, leading to the loss of function.WT embryos showed higher survival rate (81%), compared to 65% in case of nbl homozygous mutant, when subjected to 33℃. Surprisingly, 92% of nbl mutants showed a pericardial edema. Also, nbl homozygous mutants showed the sudden death around 8 months post fertilization (mpf). In 8 mpf, nbl mutants showed dilated heart and high ROS expression. mRNA expression pattern of atg5, atg3 and gabarap were found to very high in nbl homozygous compared to WT. Further, analysis of genetically unrelated patients with familial DCM, who had no mutations in the known DCM-causing genes, identified an hsp60 mutation in one DCM family in which two of four mutation prone individuals died suddenly. Over expression of nbl type or DCM patient-type mutation in Hsp60 increases autophagosomes.

研究種目 : 挑戦的萌芽研究
研究期間 : 2013～2015
課題番号 : 25670397
研究分野 : 循環器内科学