Progressive degeneration of the retina in Loxl3 mutant mouse model of Stickler syndrome

Abstract

Stickler syndrome is a multisystem collagenopathy with affected individuals exhibiting a high rate of ocular complications. Lysyl oxidase-like 3 (LOXL3) is a human disease gene candidate with a critical role in catalyzing collagen crosslinking. A homozygous missense variant of LOXL3 was reported in Stickler syndrome with severe myopia. However, the underlying mechanisms of the LOXL3 missense mutation that causes Stickler syndrome are unknown. In this study, a mouse model of Stickler syndrome induced by LOXL3 mutation (c.2027G ​> ​A, p.Cys676Try) was obtained using CRISPR/Cas9 gene editing techniques. The Loxl3 mutant mice exhibited perinatal death, spinal deformity, and cleft palate, and Loxl3 mutation also induced skeletal dysplasia and progressive visual degeneration. Furthermore, we observed the damage of the bruch's membrane (BrM) and an increase in the levels of glial fibrillary acidic protein (GFAP) and Rpe65 in the Loxl3 mutant mice. Thus, we provided the critical in vivo evidence that Loxl3 possibly has a pivotal role in maintaining the eye function.