title: Characterization of three alleles causing aspartylglycosaminuria: two from a British family and one from an American patient.
abstract: Aspartylglycosaminuria (AGU) is a lysosomal storage disease principally occurring in Finland that results from mutations in the structural gene for glycosylasparaginase (AGU). This work characterizes the inheritance of two previously reported AGU mutations in a British patient [Ikonen, Aula, Grön, Tollersrud, Halila, Manninen, Syvänen and Peltonen (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 11222-11226]. Use of the PCR determined the glycosylasparaginase cDNA sequence from both parents of the British patient and his AGU-affected brother. The father of the British AGU-affected siblings was found to be a heterozygote carrier for a C-->T point mutation which causes an Ala-->Val amino-acid substitution, while the mother was heterozygous for a 7 bp deletion that results in premature translational termination. The brother of the previously studied patient was similarly shown to be a compound heterozygote. Expression in COS-1 cells revealed the paternal Ala-->Val amino-acid substitution destroyed glycosylasparaginase catalytic activity, prevented transport of the mutant protein to the lysosome, and prevented maturation of the enzyme precursor to its native subunit structure. The Ala-->Val mutation therefore affects glycosylasparaginase in a manner similar to the Finnish AGU Cys-->Ser substitution, further supporting a linkage of glycosylasparaginase catalytic activity to its lysosomal transport and subunit processing [Fisher and Aronson (1991) J. Biol. Chem. 266, 12105-12113]. In addition, a 5 bp deletion mutation from an American patient with AGU has been characterized. The deleted sequence occurs at the beginning of the glycosylasparaginase coding sequence, resulting in an extremely truncated polypeptide. The American 5 bp deletion and the British maternal 7 bp deletion possibly decrease mRNA stability.
authors.affiliation: Department of Molecular and Cell Biology, Althouse Laboratory, Pennsylvania State University, University Park 16802.
authors.forename: H
authors.initials: H
authors.lastname: Park
authors.forename: M B
authors.initials: MB
authors.lastname: Vettese
authors.forename: A H
authors.initials: AH
authors.lastname: Fensom
authors.forename: K J
authors.initials: KJ
authors.lastname: Fisher
authors.forename: N N
authors.initials: NN
authors.lastname: Aronson
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000652:urine; D000483:Alleles; D000595:Amino Acid Sequence; D054880:Aspartylglucosaminuria; D001227:Aspartylglucosylaminase / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D014162:Transfection; D006113:United Kingdom; D014481:United States
chemical_list: C000009:N-acetylglucosaminylasparagine; D004247:DNA; D001227:Aspartylglucosylaminase; D000117:Acetylglucosamine