Identification of LRRC46 as a novel candidate gene for high myopia  

作　　者：Lingxi Jiang Chao Dai Yao Wei Bo Zhao Qi Li Zhengzheng Wu Liang Zou Zimeng Ye Zhenglin Yang Lulin Huang Yi Shi 

机构地区：[1]Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics,Department of Laboratory Medicine,Sichuan Academy of Medical Sciences&Sichuan Provincial People’s Hospital,University of Electronic Science and Technology of China,Chengdu 610072,China [2]Department of Ophthalmology,Sichuan Provincial People’s Hospital,University of Electronic Science and Technology of China,Chengdu 610072,China [3]Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences(2019RU026),Sichuan Academy of Medical Sciences&Sichuan Provincial People’s Hospital,Chengdu 610072,China [4]School of Food and Bioengineering,Chengdu University,Chengdu 610106,China [5]School of Medicine,University of Sydney,Sydney 2050,Australia [6]Jinfeng Laboratory,Chongging 400000,China

出　　处：《Science China(Life Sciences)》2024年第9期1941-1956,共16页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(82330030,82271120,82121003,82201234);the CAMS Innovation Fund for Medical Sciences(2019-12 M-5-032,2021LY06);Sichuan Science and Technology Program(2021YFS0369,2022ZYD0131,24YSZH0012,23ZYZYTS0271,TB2023093,2023ZY0059)。

摘　　要：High myopia(HM)is the primary cause of blindness,with the microstructural organization and composition of collagenous fibers in the cornea and sclera playing a crucial role in the biomechanical behavior of these tissues.In a previously reported myopic linkage region,MYP5(17q21-22),a potential candidate gene,LRRC46(c.C235T,p.Q79X),was identified in a large Han Chinese pedigree.LRRC46 is expressed in various eye tissues in humans and mice,including the retina,cornea,and sclera.In subsequent cell experiments,the mutation(c.C235T)decreased the expression of LRRC46 protein in human corneal epithelial cells(HCE-T).Further investigation revealed that Lrrc46^(-/-)mice(KO)exhibited a classical myopia phenotype.The thickness of the cornea and sclera in KO mice became thinner and more pronounced with age,the activity of limbal stem cells decreased,and microstructural changes were observed in the fibroblasts of the sclera and cornea.We performed RNA-seq on scleral and corneal tissues of KO and normal control wild-type(WT)mice,which indicated a significant downregulation of the collagen synthesis-related pathway(extracellular matrix,ECM)in KO mice.Subsequent in vitro studies further indicated that LRRC46,a member of the important LRR protein family,primarily affected the formation of collagens.This study suggested that LRRC46 is a novel candidate gene for HM,influencing collagen protein VⅢ(Col8a1)formation in the eye and gradually altering the biomechanical structure of the cornea and sclera,thereby promoting the occurrence and development of HM.

关 键 词：high myopia LRRC46 BIOMECHANICS collagen protein VⅢ 

分 类 号：R778.11[医药卫生—眼科]