講演情報
[P5-1]LARS遺伝子ノックインゼブラフィッシュを用いた乳児肝不全症候群1型における肝不全発症の病態解明
○井上 真紀1, 関口 和人1, 宮原 弘明2, 園田 翔太1, 清水 誠之3, 白石 裕士3, 前田 美和子1, 花田 礼子4, 花田 俊勝3, 井原 健二1 (1.大分大学 医学部 小児科学講座, 2.愛知医科大学 加齢医科学研究所, 3.大分大学 医学部 細胞生物学講座, 4.大分大学 医学部 神経生理学講座)
Background: Infantile liver failure syndrome type 1 (ILFS1) is a rare autosomal recessive disorder caused by biallelic variant in the leucyl-tRNA synthetase 1 gene (LARS1). The most prominent clinical finding of ILFS1 is liver failure in infancy triggered by febrile illness. Analysis of the lars-knockout zebrafish revealed that LARS deficiency caused liver failure by enhanced autophagy. However, lars-knockout zebrafish have early lethality, the mechanism underlying liver failure in infancy due to febrile illness remains unclear. This study aims to determine the mechanisms of liver failure in ILFS1 using lars-knockin zebrafish (lars-KI zebrafish).Methods: Lars-KI zebrafish with homozygote missense variant (p.I451F) identified in a patient with ILFS1 in our hospital were generated by CRISPR/Cas9 system. Lars-KI zebrafish were evaluated for liver morphology during growth. In addition, the effects of heat stress, endoplasmic reticulum (ER) stress, and ethanol stimulation on the liver were also examined.Results: Lars-KI zebrafish showed abnormal liver morphology during early growth stage. Heat stress induced hepatic abnormalities of lars-KI zebrafish, without significant difference from wild-type. Lars-KI zebrafish liver was less damaged by ER stress and more damaged by ethanol stimulation than wild-type.Conclusions: Our data clarify that the LARS1 variant induce liver damage during growth and the response of liver with LARS1 variant by various stimuli is different from that of wild-type. We further elucidate these molecular mechanisms of ILFS1 by analysis of Lars-knockin mouse.