title: The effect of a single base pair deletion (delta T525) and a C1634T missense mutation (pro545leu) on the expression of lysosomal alpha-glucosidase in patients with glycogen storage disease type II.
abstract: Glycogen storage disease type II (GSDII, Pompe's disease) is caused by an autosomal recessive inheritance of lysosomal alpha-glucosidase deficiency. By sequence analysis we have identified the mutations in the lysosomal alpha-glucosidase gene (GAA) of two unrelated patients, who have one and two copies, respectively, of the same missense mutation. The milder affected adult patient was found to be homozygous for a C1634T transition resulting in the substitution of pro545 by leu. The more severely affected adolescent patient had this same mutant allele combined with a 1 base pair deletion (delta T525) in the second allele causing premature termination at nucleotide positions 658-660. Both these mutations were introduced in wild-type alpha-glucosidase cDNA and expressed in COS-1 cells to analyse their effect. The delta T525 mutation prohibits the formation of lysosomal alpha-glucosidase completely. The pro545-->leu substitution is compatible with normal synthesis but hampers enzyme maturation and results in a 92% net loss of lysosomal alpha-glucosidase activity. The patient with adult GSDII has, in accordance with the allelic constitution, a 2-fold higher residual activity than the patient with juvenile GSDII. The delta T525 deletion was detected in two other unrelated patients, and also the C1634T transition was encountered in two more Caucasian patients with GSDII.
authors.affiliation: Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Hermans
authors.forename: E
authors.initials: E
authors.lastname: De Graaff
authors.forename: M A
authors.initials: MA
authors.lastname: Kroos
authors.forename: S
authors.initials: S
authors.lastname: Mohkamsing
authors.forename: B J
authors.initials: BJ
authors.lastname: Eussen
authors.forename: M
authors.initials: M
authors.lastname: Joosse
authors.forename: R
authors.initials: R
authors.lastname: Willemsen
authors.forename: W J
authors.initials: WJ
authors.lastname: Kleijer
authors.forename: B A
authors.initials: BA
authors.lastname: Oostra
authors.forename: A J
authors.initials: AJ
authors.lastname: Reuser
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002460:Cell Line; D002886:Chromosomes, Human, Pair 17; D005260:Female; D017353:Gene Deletion; D005087:Glucan 1,4-alpha-Glucosidase / Q000096:biosynthesis / Q000235:genetics*; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation / Q000235:genetics*; D000520:alpha-Glucosidases
chemical_list: D000520:alpha-Glucosidases; D005087:Glucan 1,4-alpha-Glucosidase