{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T22:21:13Z","timestamp":1766269273674},"reference-count":28,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2005,2,17]],"date-time":"2005-02-17T00:00:00Z","timestamp":1108598400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2005,3]]},"abstract":"<jats:p>Metachromatic leukodystrophy is a lysosomal storage disorder caused by a deficiency of arylsulfatase A (ASA). Biosynthesis studies of ASA with various structure\u2010sensitive monoclonal antibodies reveal that some epitopes of the enzyme form within the first minutes of biosynthesis whereas other epitopes form later, between 10 and 25\u2003min. When we investigated 12 various ASAs, with amino acid substitutions according to the missense mutations found in metachromatic leukodystrophy patients, immunoprecipitation with monoclonal antibodies revealed folding deficits in all 12 mutant ASA enzymes. Eleven of the 12 mutants show partial expression of the early epitopes, but only six of these show, in addition, incomplete expression of late epitopes. In none of the mutant enzymes were the late forming epitopes found in the absence of early epitopes. Thus, data from the wild\u2010type and mutant enzymes indicate that the enzyme folds in a sequential manner and that the folding of early forming epitopes is a prerequisite for maturation of the late epitopes. All mutant enzymes in which the amino acid substitution prevents the expression of the late forming epitopes are retained in the endoplasmic reticulum (ER). In contrast, all mutants in which a single late epitope is at least partially expressed can leave the ER. Thus, irrespective of the missense mutation, the expression of epitopes forming late in biosynthesis correlates with the ability of the enzyme to leave the ER. The degradation of ER\u2010retained enzymes can be reduced by inhibitors of the proteasome and ER \u03b11,2\u2010mannosidase I, indicating that all enzymes are degraded via the proteasome. Inhibition of degradation did not lead to an enhanced delivery from the ER for any of the mutant enzymes.<\/jats:p>","DOI":"10.1111\/j.1742-4658.2005.04553.x","type":"journal-article","created":{"date-parts":[[2005,2,17]],"date-time":"2005-02-17T22:21:11Z","timestamp":1108678871000},"page":"1179-1188","source":"Crossref","is-referenced-by-count":20,"title":["Missense mutations as a cause of metachromatic leukodystrophy"],"prefix":"10.1111","volume":"272","author":[{"given":"Peter","family":"Poeppel","sequence":"first","affiliation":[]},{"given":"Matthias","family":"Habetha","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Marc\u00e3o","sequence":"additional","affiliation":[]},{"given":"Heinrich","family":"B\u00fcssow","sequence":"additional","affiliation":[]},{"given":"Linda","family":"Berna","sequence":"additional","affiliation":[]},{"given":"Volkmar","family":"Gieselmann","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2005,2,17]]},"reference":[{"key":"e_1_2_15_2_2","first-page":"3695","volume-title":"The Metabolic and Molecular Bases of Inherited Disease, 8th Edn","author":"Figura 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residual arylsulfatase A (ARSA) activity in a patient with late\u2010infantile metachromatic leukodystrophy","volume":"53","author":"Kreysing J","year":"1993","journal-title":"Am J Hum Genet"},{"key":"e_1_2_15_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410310305"},{"key":"e_1_2_15_29_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20020286"}],"container-title":["The FEBS 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