フルタニ　ヨシユキ   FURUTANI Yoshiyuki   古谷　喜幸    所属   医学部 医学科（東京女子医科大学病院）    職種   非常勤講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Noonan syndrome-associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish.
掲載誌名	正式名：Molecular genetics & genomic medicine 略　 称：Mol Genet Genomic Med ISSNコード：23249269/23249269
掲載区分	国外
巻・号・頁	8(3),pp.e1107
著者・共著者	Nakagama Yu, Takeda Norihiko, Ogawa Seishi, Takeda Hiroyuki, Furutani Yoshiyuki, Nakanishi Toshio, Sato Tatsuyuki, Hirata Yoichiro, Oka Akira, Inuzuka Ryo
発行年月	2020/03
概要	BACKGROUND:Variants in the LZTR1 (leucine-zipper-like transcription regulator 1) gene (OMIM #600574) have been reported in recessive Noonan syndrome patients. In vivo evidence from animal models to support its causative role is lacking.METHODS:By CRISPR-Cas9 genome editing, we generated lztr1-mutated zebrafish (Danio rerio). Analyses of histopathology and downstream signaling were performed to investigate the pathogenesis of cardiac and extracardiac abnormalities in Noonan syndrome.RESULTS:A frameshift deletion allele was created in the zebrafish lztr1. Crosses of heterozygotes obtained homozygous lztr1 null mutants that modeled LZTR1 loss-of-function. Histological analyses of the model revealed ventricular hypertrophy, the deleterious signature of Noonan syndrome-associated cardiomyopathy. Further, assessment for extracardiac abnormalities documented multiple vascular malformations, resembling human vascular pathology caused by RAS/MAPK activation. Due to spatiotemporal regulation of LZTR1, its downstream function was not fully elucidated from western blots of adult tissue.CONCLUSION:Our novel zebrafish model phenocopied human recessive Noonan syndrome and supported the loss-of-function mechanism of disease-causing LZTR1 variants. The discovery of vascular malformations in mutants calls for the clinical follow-up of patients to monitor for its emergence. The model will serve as a novel platform for investigating the pathophysiology linking RAS/MAPK signaling to cardiac and vascular pathology.
DOI	10.1002/mgg3.1107
PMID	31883238