LRP5L-P36R Attenuating Matrix Metalloproteinase 9 Biological Function May Contribute to the Development of Cataract

Abstract

Background: Congenital cataract is the leading cause of childhood blindness. Membranous cataract is a rare congenital cataract and the mechanism has not been understood. This study aimed to investigate the pathogenic mutation and its mechanism on the development of cataract in a four-generation Chinese congenital membranous cataract family. Methods: Whole exome sequencing was performed to validate the pathogenic mutation in a Chinese congenital membranous cataract family. Wild-type and mutant LDL receptor related protein 5 like (LRP5L) plasmids were transfected into human lens epithelial cells (HLE B-3). Reverse transcription-PCR, quantitative real-time PCR, and immunoblotting were used to investigate the contributions of mutant LRP5L to development of cataract. Tube formation and spheroid sprouting assays were used to evaluate the contributions of LRP5L to angiogenesis. Findings: We found a novel suspected pathogenic mutation in LRP5L (c.107C>G, p.P36R) in a Chinese congenital membranous cataract family. In HLE B-3, LRP5L and LRP5L-P36R increase matrix metalloproteinase 9 (MMP9) expressions by cooperation with MMP9. However, LRP5L may promote angiogenesis by increasing active MMP9, while LRP5L-P36R may inhibit angiogenesis via downregulating active MMP9 and laminin γ1. Exogenous transforming growth factor beta-1 recombinant protein could promote LRP5L expressions in HLE B-3 cells. Interpretation: Our data indicated that LRP5L-P36R may contribute to the development of cataract via attenuating biological function of MMP9. This study enriches our knowledge on LRP5L and its mutant, LRP5L-P36R, and will benefit the studies on pathogenesis of congenital membranous cataract. Funding Statement: This study was supported by the Heilongjiang Provincial Natural Science Foundation of China (H2017028); the Nature Science Foundation of China (81470618); and the Natural Science Foundation of Heilongjiang Province of China (H2016038 and H2016007). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: This study was approved by the Internal Review Board of Harbin Medical University and all the experiments were conducted in accordance with Declaration of Helsinki Principles. Written informed consents were obtained from all the participants or their guardians.