{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T07:39:35Z","timestamp":1758267575308,"version":"3.44.0"},"reference-count":41,"publisher":"The Company of Biologists","issue":"10","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["F31EY033983","EY032462","EY031324","R01EY033731"],"award-info":[{"award-number":["F31EY033983","EY032462","EY031324","R01EY033731"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100013779","name":"Retina Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013779","id-type":"DOI","asserted-by":"crossref"}]},{"name":"University of Washington"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Dominant variants in inosine monophosphate dehydrogenase 1 (IMPDH1), a key enzyme in the de novo synthesis of purine bases, cause progressive photoreceptor death, leading to blindness. To investigate the cause of degeneration, we generated the first mutant IMPDH1 animal models and expressed mutant forms of impdh1a in zebrafish cone photoreceptors. Unlike cones expressing exogenous normal impdh1a, cones containing impdh1a with the K238E mutation degenerated. Cones expressing impdh1a with the D226N mutation did not show significant cone loss by 2\u2005years. Steady-state and flux metabolomics in zebrafish retinas revealed no differences in glucose shunting to the pentose phosphate pathway, no change in AMP or GMP due to D226N expression, but reduced AMP\/IMP and GMP\/IMP in K238E-expressing cones. cGMP levels were normal in both mutant retinas. Further, pde6cw59; impdh1asa23234 double mutant cones were not rescued from degeneration. Both K238E and D226N mutant-containing proteins formed abnormally large mislocalized filaments, which could disrupt normal dynamic protein\u2013protein interactions. Our work disproves the model of a hyperactive enzyme leading to elevated cGMP causing cell death and reveals new defects associated with IMPDH1 mutant expression.<\/jats:p>","DOI":"10.1242\/dmm.052389","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T09:02:57Z","timestamp":1755507777000},"source":"Crossref","is-referenced-by-count":1,"title":["Retinopathy-associated inosine monophosphate dehydrogenase 1 mutations cause metabolic and filament defects in cones"],"prefix":"10.1242","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4255-1404","authenticated-orcid":false,"given":"Kaitlyn M.","family":"Rutter","sequence":"first","affiliation":[{"name":"University of Washington 1 Department of Biochemistry , , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3344-4268","authenticated-orcid":false,"given":"Michelle M.","family":"Giarmarco","sequence":"additional","affiliation":[{"name":"University of Washington 2 Department of Ophthalmology , , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1729-8261","authenticated-orcid":false,"given":"Vivian","family":"Truong","sequence":"additional","affiliation":[{"name":"University of Washington 2 Department of Ophthalmology , , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yekai","family":"Wang","sequence":"additional","affiliation":[{"name":"West Virginia University 3 Department of Biochemistry and Molecular Medicine , , Morgantown, WV 26506 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Eminhizer","sequence":"additional","affiliation":[{"name":"West Virginia University 3 Department of Biochemistry and Molecular Medicine , , Morgantown, WV 26506 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinxiao","family":"Xiang","sequence":"additional","affiliation":[{"name":"West Virginia University 3 Department of Biochemistry and Molecular Medicine , , Morgantown, WV 26506 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Whitney M.","family":"Cleghorn","sequence":"additional","affiliation":[{"name":"University of Washington 1 Department of Biochemistry , , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gardenia","family":"Sanchez","sequence":"additional","affiliation":[{"name":"University of Washington 1 Department of Biochemistry , , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anika L.","family":"Burrell","sequence":"additional","affiliation":[{"name":"University of Washington 1 Department of Biochemistry , , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin M.","family":"Kollman","sequence":"additional","affiliation":[{"name":"University of Washington 1 Department of Biochemistry , , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhai","family":"Du","sequence":"additional","affiliation":[{"name":"West Virginia University 3 Department of Biochemistry and Molecular Medicine , , Morgantown, WV 26506 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9851-5525","authenticated-orcid":false,"given":"Susan E.","family":"Brockerhoff","sequence":"additional","affiliation":[{"name":"University of Washington 1 Department of Biochemistry , , Seattle, WA 98195 ,","place":["USA"]},{"name":"University of Washington 2 Department of Ophthalmology , , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"2025091708280504300_DMM052389C1","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1093\/hmg\/ddh061","article-title":"On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa","volume":"13","author":"Aherne","year":"2004","journal-title":"Hum. 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