{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:27:16Z","timestamp":1792099636207,"version":"4.4.0"},"reference-count":32,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2005,1,1]],"date-time":"2005-01-01T00:00:00Z","timestamp":1104537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009396","name":"Universit\u00e4tsSpital Z\u00fcrich","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009396","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009396","name":"Universit\u00e4tsSpital Z\u00fcrich","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009396","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2005,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Mutations in proteins that induce misfolding and proteasomal degradation are common causes of inherited diseases. Fabry disease is a lysosomal storage disorder caused by a deficiency of \u03b1\u2010galac\u2010 tosidase A activity in lysosomes resulting in an accumulation of glycosphingolipid globotriosylceramide (Gb3). Some classical Fabry hemizygotes and all cardiac variants have residual \u03b1\u2010galactosidase A activity, but the mutant enzymes are unstable. Such mutant enzymes appear to be misfolded, recognized by the ER protein quality control, and degraded before sorting into lyso\u2010 somes. Hence, correction of the trafficking defect of mutant but catalytically active enzyme into lysosomes would be beneficial for treatment of the disease. Here we show that a nontoxic competitive inhibitor (1\u2010deox\u2010 ygalactonojirimycin) of \u03b1\u2010galactosidase A functions as a chemical chaperone by releasing ER\u2010retained mutant enzyme from BiP. The treatment with subinhibitory doses resulted in efficient, long\u2010term lysosomal trafficking of the ER\u2010retained mutant \u03b1\u2010galactosidase A. Suc\u00accessful clearance of lysosomal Gb3 storage and a near\u2010normal lysosomal phenotype was achieved in human Fabry fibroblasts harboring different types of mutations. Small molecule chemical chaperones will be therapeutically useful for various lysosomal storage disorders as well as for other genetic metabolic disorders caused by mutant but nonetheless catalytically active enzymes.\u2014Yam, G. H.\u2010F., Zuber, C., Roth, J. A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    19, 12\u201018 (2005)\n                  <\/jats:p>","DOI":"10.1096\/fj.04-2375com","type":"journal-article","created":{"date-parts":[[2005,1,3]],"date-time":"2005-01-03T18:33:18Z","timestamp":1104777198000},"page":"12-18","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":142,"title":["A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder"],"prefix":"10.1096","volume":"19","author":[{"given":"Gary Hin-Fai","family":"Yam","sequence":"first","affiliation":[{"name":"Division of Cell and Molecular Pathology, Department of Pathology University of Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Zuber","sequence":"additional","affiliation":[{"name":"Division of Cell and Molecular Pathology, Department of Pathology University of Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Roth","sequence":"additional","affiliation":[{"name":"Division of Cell and Molecular Pathology, Department of Pathology University of Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,1]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.35.102401.090313"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1068408"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02261"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1006\/scdb.1999.0318"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(00)00168-8"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.288.5464.331"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1052"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02263"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr000423j"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02265"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.7.1628"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0502-485"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/rwgn.2001.0443"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00484919"},{"key":"e_1_2_5_16_1","first-page":"71A","article-title":"Fabry disease: an asymptomatic hemizygote with significant residual \u03b1-galacto- sidase A activity","volume":"33","author":"Bishop D.","year":"1981","journal-title":"Am. 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