TAILIEUCHUNG - Báo cáo khoa học: Missense mutations as a cause of metachromatic leukodystrophy Degradation of arylsulfatase A in the endoplasmic reticulum

Metachromatic leukodystrophy is a lysosomal storage disorder caused by a deficiency of arylsulfatase A (ASA). Biosynthesis studies of ASA with vari-ous structure-sensitive monoclonal antibodies reveal that some epitopes of the enzyme form within the first minutes of biosynthesis whereas other epi-topes form later, between 10 and 25 min. 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 | ềFEBS Journal Missense mutations as a cause of metachromatic leukodystrophy Degradation of arylsulfatase A in the endoplasmic reticulum Peter Poeppel1 Matthias Habetha2 Ana Marcao3 Heinrich Bussow4 Linda Berna5 and Volkmar Gieselmann1 1 Institut fur Physiologische Chemie Rheinische-Friedrich-Wilhelms Universitat Bonn Germany 2 Zoologisches Institut Christian-Albrechts-Universitat zu Kiel Germany 3 Instituto de Biologia Molecular e Celular University of Porto Portugal 4 Institut fur Anatomie Rheinische-Friedrich-Wilhelms Universitat Bonn Germany 5 Institute of Inherited Metabolic Disorders Charles University Prague Czech Republic Keywords ERAD proteasomaldegradation arylsulfatase A metachromatic leukodystrophy Correspondence V. Gieselmann Institut fur Physiologische Chemie Rheinische-Friedrich-Wilhelms Universitat Bonn Nussallee 11 53115 Bonn Germany Fax 49 22 873 2416 Tel 49 22 873 2411 E-mail gieselmann@. Note P. Poeppeland M. Habetha contributed equally to this work. Received 29 October 2004 revised 14 December 2004 accepted 4 January 2005 doi Metachromatic leukodystrophy is a lysosomal storage disorder caused by a deficiency of arylsulfatase A ASA . Biosynthesis studies of ASA with various structure-sensitive 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 min. 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-type and .

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