{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:08:52Z","timestamp":1791493732227,"version":"4.3.4"},"reference-count":38,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2006,4]]},"abstract":"<jats:p>Fabry disease is a lysosomal storage disorder caused by deficiency of \u03b1-galactosidase A (\u03b1-Gal A) resulting in lysosomal accumulation of glycosphingolipid globotriosylceramide Gb3. Misfolded \u03b1-Gal A variants can have residual enzyme activity but are unstable. Their lysosomal trafficking is impaired because they are retained in the endoplasmic reticulum (ER) by quality control. Subinhibitory doses of the competitive inhibitor of \u03b1-Gal A, 1-deoxygalactonojirimycin (DGJ), stabilize mutant \u03b1-Gal A in vitro and correct the trafficking defect. We showed by immunolabeling that the chaperone-like action of DGJ significantly reduces the lysosomal Gb3 storage in human Fabry fibroblasts harboring the novel mutations T194I and V390fsX8. The specificity of the DGJ effect was proven by RNA interference. Electron microscopic morphometry demonstrated a reduction of large-size, disease-associated lysosomes and loss of characteristic multilamellar lysosomal inclusions on DGJ treatment. In addition, the pre-Golgi intermediates were decreased. However, the rough ER was not different between DGJ-treated and untreated cells. Pulse-chase experiments revealed that DGJ treatment resulted in maturation and stabilization of mutant \u03b1-Gal A. Genes involved in cell stress signaling, heat shock response, unfolded protein response, and ER-associated degradation show no apparent difference in expression between untreated and DGJ-treated fibroblasts. The DGJ treatment has no apparent cytotoxic effects. Thus our data show the usefulness of a pharmacological chaperone for correction of the lysosomal storage in Fabry fibroblasts harboring different mutations with residual enzyme activity. Pharmacological chaperones acting on misfolded, unstable mutant proteins that exhibit residual biological activity offer a convenient and cost-efficient therapeutic strategy.<\/jats:p>","DOI":"10.1152\/ajpcell.00426.2005","type":"journal-article","created":{"date-parts":[[2006,3,10]],"date-time":"2006-03-10T15:18:13Z","timestamp":1142003893000},"page":"C1076-C1082","source":"Crossref","is-referenced-by-count":107,"title":["Pharmacological chaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants"],"prefix":"10.1152","volume":"290","author":[{"given":"Gary Hin-Fai","family":"Yam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Bosshard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Zuber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beat","family":"Steinmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"crossref","unstructured":"Ahner A\n                      and Brodsky JL.\n                      Checkpoints in ER-associated degradation: excuse me, which way to the proteasome?\n                      Trends Cell Biol\n                      14\n                      : 474\u2013478, 2004.","DOI":"10.1016\/j.tcb.2004.07.013"},{"key":"R2","doi-asserted-by":"crossref","unstructured":"Aridor M\n                      and Hannan LA.\n                      Traffic jams II: an update of diseases of intracellular transport.\n                      Traffic\n                      3\n                      : 781\u2013790, 2002.","DOI":"10.1034\/j.1600-0854.2002.31103.x"},{"key":"R3","doi-asserted-by":"crossref","unstructured":"Asano N\n                      , Ishii S, Kizu H, Ikeda K, Yasuda K, Kato A, Martin OR, and Fan JQ.\n                      In vitro inhibition and intracellular enhancement of lysosomal \u03b1-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives.\n                      Eur J Biochem\n                      267\n                      : 4179\u20134186, 2000.","DOI":"10.1046\/j.1432-1327.2000.01457.x"},{"key":"R4","doi-asserted-by":"crossref","unstructured":"Brady RO\n                      .\n                      Gaucher and Fabry diseases: from understanding pathophysiology to rational therapies.\n                      Acta Paediatr Suppl\n                      92\n                      : 19\u201324, 2003.","DOI":"10.1111\/j.1651-2227.2003.tb00215.x"},{"key":"R5","doi-asserted-by":"crossref","unstructured":"Butters TD\n                      , Mellor HR, Narita K, Dwek RA, and Platt FM.\n                      Small-molecule therapeutics for the treatment of glycolipid lysosomal storage disorders.\n                      Philos Trans R Soc Lond B Biol Sci\n                      358\n                      : 927\u2013945, 2003.","DOI":"10.1098\/rstb.2003.1278"},{"key":"R6","doi-asserted-by":"crossref","unstructured":"Cox T\n                      , Lachmann R, Hollak C, Aerts J, van Weely S, Hrebicek M, Platt F, Butters T, Dwek R, Moyses C, Gow I, Elstein D, and Zimran A.\n                      Novel oral treatment of Gaucher's disease with\n                      N\n                      -butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.\n                      Lancet\n                      355\n                      : 1481\u20131485, 2000.","DOI":"10.1016\/S0140-6736(00)02161-9"},{"key":"R7","unstructured":"Desnick R\n                      , Ioannou Y, and Eng C.\n                      \u03b1-Galactosidase A deficiency: Fabry disease. 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