EAAT1 variants associated with glaucoma

• Published in: Biochemical and biophysical research communications 2020-09, Vol.529 (4), p.943-949
• Main Authors: Yanagisawa, Michiko, Namekata, Kazuhiko, Aida, Tomomi, Katou, Sayaka, Takeda, Takuya, Harada, Takayuki, Fuse, Nobuo, the Glaucoma Gene Research Group, Tanaka, Kohichi
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Sequence; Animals; Case-Control Studies; Cell Line; EAAT1; Excitatory Amino Acid Transporter 1 - deficiency; Excitatory Amino Acid Transporter 1 - genetics; Excitotoxicity; Gene Expression; Gene Frequency; Glaucoma; Glaucoma, Open-Angle - genetics; Glaucoma, Open-Angle - metabolism; Glaucoma, Open-Angle - pathology; Glutamate transporter; Humans; Intraocular Pressure; Low Tension Glaucoma - genetics; Low Tension Glaucoma - metabolism; Low Tension Glaucoma - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Missense mutation; Mutation, Missense; Optic Nerve - metabolism; Optic Nerve - pathology; Retina; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - pathology; Risk Factors; Sequence Alignment; Sequence Homology, Amino Acid; Silent Mutation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.06.099

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. •We identify 8 rare variants in EAAT1 that were overrepresented in glaucoma patients.•Loss-of-function EAAT1 variants, A169G and A329T, are found in glaucoma patients.•EAAT1 variants (A169G and A329T) sensitize retinal ganglion cells to excitotoxicity.