EAAT1 variants associated with glaucoma

Michiko Yanagisawa; Kazuhiko Namekata; Tomomi Aida; Sayaka Katou; Takuya Takeda; Takayuki Harada; Nobuo Fuse; The Glaucoma Gene Research Group; Kohichi Tanaka

doi:10.1016/j.bbrc.2020.06.099

EAAT1 variants associated with glaucoma

Biochem Biophys Res Commun. 2020 Sep 3;529(4):943-949. doi: 10.1016/j.bbrc.2020.06.099. Epub 2020 Jul 30.

Authors

Michiko Yanagisawa¹, Kazuhiko Namekata², Tomomi Aida¹, Sayaka Katou¹, Takuya Takeda¹, Takayuki Harada², Nobuo Fuse³, The Glaucoma Gene Research Group⁴, Kohichi Tanaka⁵

Affiliations

¹ Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
² Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
³ Department of Integrative Genomics, Tohoku Medical Megabank Organization, Sendai, Japan; Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan.
⁴ Investigators in the Glaucoma Gene Research Group are Listed in the Supplementary Appendix, Japan.
⁵ Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan; The Center for Brain Integration Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address: tanaka.aud@mri.tmd.ac.jp.

PMID: 32819603
DOI: 10.1016/j.bbrc.2020.06.099

Abstract

Glaucoma is one of the leading causes of blindness characterized by progressive loss of retinal ganglion cells (RGCs) and their axons. We reported that glutamate/aspartate transporter (GLAST) knockout mice showed progressive RGC loss and optic nerve degeneration that are similar to glaucoma. To explore the possibility that rare variants in the EAAT1 gene (the human homolog of GLAST) cause susceptibility to glaucoma, we performed targeted sequencing of EAAT1 in 440 patients with glaucoma and 450 control subjects. We identified 8 rare variants in 20 out of 440 patients, including 4 synonymous and 4 missense variants located at protein coding regions. One of these rare variants (rs117295512) showed significant association with the risk of glaucoma (OR = 10.44, P = 0.005). Furthermore, the allele frequency for loss-of-function EAAT1 variants, pAla169Gly and pAla329Thr, was 5.5 folds higher in the glaucoma (1.1%) compared with the control cohort (0.2%). These findings suggest that these rare variants may contribute to the pathogenesis of glaucoma and that loss-of-function variants in EAAT1 are present in a small number of patients with glaucoma.

Keywords: EAAT1; Excitotoxicity; Glaucoma; Glutamate transporter; Missense mutation; Retina.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Amino Acid Sequence
Animals
Case-Control Studies
Cell Line
Excitatory Amino Acid Transporter 1 / deficiency
Excitatory Amino Acid Transporter 1 / genetics*
Gene Expression
Gene Frequency
Glaucoma, Open-Angle / genetics*
Glaucoma, Open-Angle / metabolism
Glaucoma, Open-Angle / pathology
Humans
Intraocular Pressure
Low Tension Glaucoma / genetics*
Low Tension Glaucoma / metabolism
Low Tension Glaucoma / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation, Missense*
Optic Nerve / metabolism
Optic Nerve / pathology
Retinal Ganglion Cells / metabolism
Retinal Ganglion Cells / pathology
Risk Factors
Sequence Alignment
Sequence Homology, Amino Acid
Silent Mutation*

Substances

Excitatory Amino Acid Transporter 1
SLC1A3 protein, human
Slc1a3 protein, mouse