AUTHOR=Zhao Minglei , Mei Tingfang , Shang Bizhi , Zou Bin , Lian Qing , Xu Wenchang , Wu Keling , Lai Yuhua , Liu Chujun , Wei Lai , Zhu Jie , Zhang Kang , Liu Yizhi , Zhao Ling 

TITLE=Defect of LSS Disrupts Lens Development in Cataractogenesis

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.788422

DOI=10.3389/fcell.2021.788422

ISSN=2296-634X

ABSTRACT=Congenital cataract is one of the leading causes of blindness in children worldwide. About one third of congenital cataracts are caused by genetic defects. LSS, which encodes Lanosterol synthase, is a causal gene for congenital cataracts. LSS is critical in preventing abnormal protein aggregation of various cataract-causing mutant crystallins, however, its roles in lens development remains largely unknown. In our study, we generated a mouse model harboring Lss G589S mutation, which is homologous to cataract-causing G588S mutation in human LSS. LssG589S/G589S mice exhibited neonatal lethality at postal day 0 (P0), whereas these mice showed severe opacity in eye lens. Also, we found that cataract was formed at E17.5 after we examined the opacity of embryonic lens from E13.5-E18.5. Moreover, disrupted lens differentiation occurred at E14.5 prior to opacity of eye lens was formed, shown as delayed differentiation of lens secondary fiber and disordered lens fibers organization. In addition, RNA-seq analysis indicated that cholesterol synthesis signaling pathways were significantly downregulated. Overall, our findings provide clear evidence that a mouse model harboring a homozygous Lss G589S mutation can recapitulate human congenital cataract. Our study points out that LSS functions as a critical determinant of lens development, which will contribute to better understand LSS defects in cataractogenesis and develop therapies for cataract.