Human Molecular Genetics, 2001, Vol. 10, No. 9 983-995
© 2001 Oxford University Press
Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations
1Department of Medical Genetics, University of Helsinki and Department of Molecular Medicine, National Public Health Institute, Haartmaninkatu 8, P.O. Box 104, FIN-00251 Helsinki, Finland, 2Department of Chemistry, University of Joensuu, P.O. Box 111, FIN-87101 Joensuu, Finland and 3Department of Human Genetics, UCLA School of Medicine, 695 Charles E. Young Drive South, Box 708822, Los Angeles, CA 90095-7088, USA
A deficiency of functional aspartylglucosaminidase (AGA) causes a lysosomal storage disease, aspartylglucosaminuria (AGU). The recessively inherited disease is enriched in the Finnish population, where 98% of AGU alleles contain one founder mutation, AGUFin. Elsewhere in the world, we and others have described 18 different sporadic AGU mutations. Many of these are predicted to interfere with the complex intracellular maturation and processing of the AGA polypeptide. Proper initial folding of AGA in the endoplasmic reticulum (ER) is dependent on intramolecular disulfide bridge formation and dimerization of two precursor polypeptides. The subsequent activation of AGA occurs autocatalytically in the ER and the protein is transported via the Golgi to the lysosomal compartment using the mannose-6-phosphate receptor pathway. Here we use the three-dimensional structure of AGA to predict structural consequences of AGU mutations, including six novel mutations, and make an effort to characterize every known disease mutation by dissecting the effect of mutations on intracellular stability, maturation, transport and the activity of AGA. Most mutations are substitutions replacing the original amino acid with a bulkier residue. Mutations of the dimer interface prevent dimerization in the ER, whereas active site mutations not only destroy the activity but also affect maturation of the precursor. Depending on their effects on the AGA polypeptide the mutations can be categorized as mild, moderate or severe. These data contribute to the expanding body of knowledge pertaining to molecular pathogenesis of AGU.
+ To whom correspondence should be addressed. Tel: +1 310 794 5631; Fax: +1 310 794 5446; Email: lpeltonen@mednet.ucla.edu
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