Defect of LSS Disrupts Lens Development in Cataractogenesis.

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

doi:10.3389/fcell.2021.788422

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 remain 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 to E18.5. Moreover, disrupted lens differentiation occurred at E14.5 prior to formation of the opacity of eye lens, shown as delayed differentiation of lens secondary fiber and disordered lens fiber 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 understanding LSS defects in cataractogenesis and developing therapies for cataracts.

Highlights

Cataracts occur due to a loss of transparency in the crystalline lens of the eye, which is the most leading cause of blindness and impaired vision worldwide (Liu et al, 2017)
Disrupted lens structure caused by a homozygous LssG589S/G589S mutation at postal day 0 (P0)
The pups with a homozygous LssG589S/G589S mutation were born with abnormally small lenses with severely structural defects at P0, while the lens structure is normal in WT and LssG589S/+ mice at P0 (Figure 2A)

Summary

Introduction

Cataracts occur due to a loss of transparency in the crystalline lens of the eye, which is the most leading cause of blindness and impaired vision worldwide (Liu et al, 2017). Up to one-third of congenital cataracts (CC) are inherited (Hejtmancik, 2008). Mutations in genes encoding membrane transport, scaffolding proteins, transcription factors, heat shock transcription factor, and metabolism-related proteins are identified to cause CC (Shiels and Hejtmancik, 2013; Zhao et al, 2015; Sun et al, 2019). Red arrows indicated congenital cataract formed in lens of LssG589S/G589S mice at P0. Red arrows indicated cataract formed in the lens of LssG589S/G589S mice at P0

Methods

Results

Conclusion