Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations

A deficiency of functional aspartylglucosaminidase (AGA) causes a lysosomal storage disease, aspartylglucosaminuria (AGU), The recessively inherited d isease is enriched in the Finnish population, where 98% of AGU alleles cont ain one founder mutation, AGU(Fin). Elsewhere in the world, we and others h ave described 18 different sporadic AGU mutations, Many of these are predic ted to interfere with the complex intracellular maturation and processing o f the AGA polypeptide, Proper initial folding of AGA in the endoplasmic ret iculum (ER) is dependent on intramolecular disulfide bridge formation and d imerization 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 p athway. Here we use the three-dimensional structure of AGA to predict struc tural consequences of AGU mutations, including six novel mutations, and mak e an effort to characterize every known disease mutation by dissecting the effect of mutations on intracellular stability, maturation, transport and t he activity of AGA. Most mutations are substitutions replacing the original amino acid with a bulkier residue. Mutations of the dimer interface preven t dimerization in the ER, whereas active site mutations not only destroy th e activity but also affect maturation of the precursor. Depending on their effects on the AGA polypeptide the mutations can be categorized as mild, mo derate or severe, These data contribute to the expanding body of knowledge pertaining to molecular pathogenesis of AGU.