EAAT1 variants associated with glaucoma
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 expl...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2020-09, Vol.529 (4), p.943-949 |
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| creator | Yanagisawa, Michiko Namekata, Kazuhiko Aida, Tomomi Katou, Sayaka Takeda, Takuya Harada, Takayuki Fuse, Nobuo the Glaucoma Gene Research Group Tanaka, Kohichi |
| description | 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. |
| doi_str_mv | 10.1016/j.bbrc.2020.06.099 |
| format | Article |
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•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.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1016/j.bbrc.2020.06.099</identifier><identifier>PMID: 32819603</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>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</subject><ispartof>Biochemical and biophysical research communications, 2020-09, Vol.529 (4), p.943-949</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-318037e67233702027fe0818e9fa513b611e9592ea39746d37a3fa91648e398b3</citedby><cites>FETCH-LOGICAL-c356t-318037e67233702027fe0818e9fa513b611e9592ea39746d37a3fa91648e398b3</cites><orcidid>0000-0003-0237-4746 ; 0000-0001-5835-0626</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bbrc.2020.06.099$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32819603$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yanagisawa, Michiko</creatorcontrib><creatorcontrib>Namekata, Kazuhiko</creatorcontrib><creatorcontrib>Aida, Tomomi</creatorcontrib><creatorcontrib>Katou, Sayaka</creatorcontrib><creatorcontrib>Takeda, Takuya</creatorcontrib><creatorcontrib>Harada, Takayuki</creatorcontrib><creatorcontrib>Fuse, Nobuo</creatorcontrib><creatorcontrib>the Glaucoma Gene Research Group</creatorcontrib><creatorcontrib>Tanaka, Kohichi</creatorcontrib><title>EAAT1 variants associated with glaucoma</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>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.</description><subject>Alleles</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Case-Control Studies</subject><subject>Cell Line</subject><subject>EAAT1</subject><subject>Excitatory Amino Acid Transporter 1 - deficiency</subject><subject>Excitatory Amino Acid Transporter 1 - genetics</subject><subject>Excitotoxicity</subject><subject>Gene Expression</subject><subject>Gene Frequency</subject><subject>Glaucoma</subject><subject>Glaucoma, Open-Angle - genetics</subject><subject>Glaucoma, Open-Angle - metabolism</subject><subject>Glaucoma, Open-Angle - pathology</subject><subject>Glutamate transporter</subject><subject>Humans</subject><subject>Intraocular Pressure</subject><subject>Low Tension Glaucoma - genetics</subject><subject>Low Tension Glaucoma - metabolism</subject><subject>Low Tension Glaucoma - pathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Missense mutation</subject><subject>Mutation, Missense</subject><subject>Optic Nerve - metabolism</subject><subject>Optic Nerve - pathology</subject><subject>Retina</subject><subject>Retinal Ganglion Cells - metabolism</subject><subject>Retinal Ganglion Cells - pathology</subject><subject>Risk Factors</subject><subject>Sequence Alignment</subject><subject>Sequence Homology, Amino Acid</subject><subject>Silent Mutation</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kD1PwzAQhi0EoqXwBxhQNlgS7uzEiSWWqiofUiWWIrFZjnMBV0kDdlrEvydVCyPTLe_73N3D2CVCgoDydpWUpbcJBw4JyASUOmJjBAUxR0iP2RgAZMwVvo7YWQgrAMRUqlM2ErxAJUGM2fV8Ol1itDXemXUfIhNCZ53pqYq-XP8evTVmY7vWnLOT2jSBLg5zwl7u58vZY7x4fniaTRexFZnsY4EFiJxkzoXIh7t4XhMUWJCqTYailIikMsXJCJWnshK5EbVRKNOChCpKMWE3e-6H7z43FHrdumCpacyauk3QPBVSqEwMCyaM76PWdyF4qvWHd63x3xpB7wTpld4J0jtBGqQeBA2lqwN_U7ZU_VV-jQyBu32Ahi-3jrwO1tHaUuU82V5XnfuP_wPjgXNq</recordid><startdate>20200903</startdate><enddate>20200903</enddate><creator>Yanagisawa, Michiko</creator><creator>Namekata, Kazuhiko</creator><creator>Aida, Tomomi</creator><creator>Katou, Sayaka</creator><creator>Takeda, Takuya</creator><creator>Harada, Takayuki</creator><creator>Fuse, Nobuo</creator><creator>the Glaucoma Gene Research Group</creator><creator>Tanaka, Kohichi</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0237-4746</orcidid><orcidid>https://orcid.org/0000-0001-5835-0626</orcidid></search><sort><creationdate>20200903</creationdate><title>EAAT1 variants associated with glaucoma</title><author>Yanagisawa, Michiko ; Namekata, Kazuhiko ; Aida, Tomomi ; Katou, Sayaka ; Takeda, Takuya ; Harada, Takayuki ; Fuse, Nobuo ; the Glaucoma Gene Research Group ; Tanaka, Kohichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-318037e67233702027fe0818e9fa513b611e9592ea39746d37a3fa91648e398b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Alleles</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Case-Control Studies</topic><topic>Cell Line</topic><topic>EAAT1</topic><topic>Excitatory Amino Acid Transporter 1 - deficiency</topic><topic>Excitatory Amino Acid Transporter 1 - genetics</topic><topic>Excitotoxicity</topic><topic>Gene Expression</topic><topic>Gene Frequency</topic><topic>Glaucoma</topic><topic>Glaucoma, Open-Angle - genetics</topic><topic>Glaucoma, Open-Angle - metabolism</topic><topic>Glaucoma, Open-Angle - pathology</topic><topic>Glutamate transporter</topic><topic>Humans</topic><topic>Intraocular Pressure</topic><topic>Low Tension Glaucoma - genetics</topic><topic>Low Tension Glaucoma - metabolism</topic><topic>Low Tension Glaucoma - pathology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Missense mutation</topic><topic>Mutation, Missense</topic><topic>Optic Nerve - metabolism</topic><topic>Optic Nerve - pathology</topic><topic>Retina</topic><topic>Retinal Ganglion Cells - metabolism</topic><topic>Retinal Ganglion Cells - pathology</topic><topic>Risk Factors</topic><topic>Sequence Alignment</topic><topic>Sequence Homology, Amino Acid</topic><topic>Silent Mutation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yanagisawa, Michiko</creatorcontrib><creatorcontrib>Namekata, Kazuhiko</creatorcontrib><creatorcontrib>Aida, Tomomi</creatorcontrib><creatorcontrib>Katou, Sayaka</creatorcontrib><creatorcontrib>Takeda, Takuya</creatorcontrib><creatorcontrib>Harada, Takayuki</creatorcontrib><creatorcontrib>Fuse, Nobuo</creatorcontrib><creatorcontrib>the Glaucoma Gene Research Group</creatorcontrib><creatorcontrib>Tanaka, Kohichi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yanagisawa, Michiko</au><au>Namekata, Kazuhiko</au><au>Aida, Tomomi</au><au>Katou, Sayaka</au><au>Takeda, Takuya</au><au>Harada, Takayuki</au><au>Fuse, Nobuo</au><au>the Glaucoma Gene Research Group</au><au>Tanaka, Kohichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EAAT1 variants associated with glaucoma</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2020-09-03</date><risdate>2020</risdate><volume>529</volume><issue>4</issue><spage>943</spage><epage>949</epage><pages>943-949</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><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.
•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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32819603</pmid><doi>10.1016/j.bbrc.2020.06.099</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-0237-4746</orcidid><orcidid>https://orcid.org/0000-0001-5835-0626</orcidid></addata></record> |
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| 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 |
| title | EAAT1 variants associated with glaucoma |
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