{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T06:08:24Z","timestamp":1793858904926,"version":"4.6.1"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"8","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,2,26]]},"abstract":"<jats:p>Fabry disease is an X-linked lysosomal storage disease caused by deficiency of \u03b1-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of \u03b1-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder.<\/jats:p>","DOI":"10.1073\/pnas.0712309105","type":"journal-article","created":{"date-parts":[[2008,2,19]],"date-time":"2008-02-19T23:33:56Z","timestamp":1203464036000},"page":"2812-2817","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":674,"title":["Elevated globotriaosylsphingosine is a hallmark of Fabry disease"],"prefix":"10.1073","volume":"105","author":[{"given":"Johannes M.","family":"Aerts","sequence":"first","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna E.","family":"Groener","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijmen","family":"Kuiper","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilma E.","family":"Donker-Koopman","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke","family":"Strijland","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roelof","family":"Ottenhoff","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"van Roomen","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Mirzaian","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits A.","family":"Wijburg","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor E.","family":"Linthorst","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anouk C.","family":"Vedder","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia M.","family":"Rombach","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josanne","family":"Cox-Brinkman","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pentti","family":"Somerharju","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, Department of Biochemistry, University of Helsinki, Haartmaninkatu 8, PL 63, 00014, Helsinki, Finland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf G.","family":"Boot","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla E.","family":"Hollak","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roscoe O.","family":"Brady","sequence":"additional","affiliation":[{"name":"Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, 9000 Rockville Pike, Bethesda, MD 20892-1260"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben J.","family":"Poorthuis","sequence":"additional","affiliation":[{"name":"*Amsterdam Lysosome Center, Departments of Medical Biochemistry, Internal Medicine, and Paediatrics, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,2,26]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196705252762101"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.167.3922.1268"},{"key":"e_1_3_3_3_2","first-page":"3733","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Desnick RJ","year":"2001","unstructured":"RJ Desnick, YA Ioannou, \u03b1-Galactosidase A deficiency: Fabry disease. The Metabolic and Molecular Bases of Inherited Disease, eds R Scriver, et al. (McGraw-Hill, New York), pp. 3733\u20133774 (2001)."},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197307052890103"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.285.21.2743"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200107053450102"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000598"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012447102358"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012993305223"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.036327"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.md.0000178976.62537.6b"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-006-0484-8"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-006-0196-0"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.6.2540"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1080\/08035320510028111"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.2174\/187152506778520718"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000209649.60409.38"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1096-7192(02)00117-8"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1982.tb07950.x"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-7735-1_8"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)39839-4"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6719111"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022436928925"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2003.08.016"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1139\/y59-099"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2006.079012"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2760(72)90077-X"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03401671"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-006-0340-x"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1080\/08035320600618924"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00924.x"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-005-4415-x"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2007.06.013"},{"key":"e_1_3_3_34_2","first-page":"249","article-title":"Biochemical outcome of successful renal transplantation in a Fabry patient.","volume":"200","author":"Van den Bergh FA","year":"1976","unstructured":"FA Van den Bergh, PJ Rietra, AJ Kolk-Vegter, E Bosch, JM Tager, Biochemical outcome of successful renal transplantation in a Fabry patient. Acta Med Scand 200, 249\u2013256 (1976).","journal-title":"Acta Med Scand"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-199104000-00004"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-007-0468-6"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1992.tb08460.x"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)69582-1"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405432200"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.2007.00207.x"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1086\/345309"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(75)90488-1"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0712309105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T16:36:42Z","timestamp":1649781402000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0712309105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,2,26]]},"references-count":42,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2008,2,26]]}},"alternative-id":["10.1073\/pnas.0712309105"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0712309105","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,2,26]]},"assertion":[{"value":"2007-12-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-02-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}