Genome-wide association study and whole-genome sequencing identify a deletion in LRIT3 associated with canine congenital stationary night blindness.

• 影响指数: 4.996
• 发表时间: 10 2019 2
• 来源期刊: Sci Rep
• DOI: 10.1038/s41598-019-50573-7
• PMID: 31578364
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 综合性期刊
• 作者列表: Das RG,Becker D,Jagannathan V,Goldstein O,Santana E,Carlin K,Sudharsan R,Leeb T,Nishizawa Y,Kondo M,Aguirre GD,Miyadera K

Mesh: Animals; Chromosomes / genetics; Dog Diseases / genetics; Dogs; Eye Diseases, Hereditary / genetics veterinary; Female; Gene Deletion; Genetic Diseases, X-Linked / genetics veterinary; Genome-Wide Association Study; Heterozygote; Male; Membrane Proteins / genetics metabolism; Myopia / genetics veterinary; Night Blindness / genetics veterinary; Retina / metabolism pathology; Whole Genome Sequencing

Abstract

Congenital stationary night blindness (CSNB), in the complete form, is caused by dysfunctions in ON-bipolar cells (ON-BCs) which are secondary neurons of the retina. We describe the first disease causative variant associated with CSNB in the dog. A genome-wide association study using 12 cases and 11 controls from a research colony determined a 4.6 Mb locus on canine chromosome 32. Subsequent whole-genome sequencing identified a 1 bp deletion in LRIT3 segregating with CSNB. The canine mutant LRIT3 gives rise to a truncated protein with unaltered subcellular expression in vitro. Genetic variants in LRIT3 have been associated with CSNB in patients although there is limited evidence regarding its apparently critical function in the mGluR6 pathway in ON-BCs. We determine that in the canine CSNB retina, the mutant LRIT3 is correctly localized to the region correlating with the ON-BC dendritic tips, albeit with reduced immunolabelling. The LRIT3-CSNB canine model has direct translational potential enabling studies to help understand the CSNB pathogenesis as well as to develop new therapies targeting the secondary neurons of the retina.