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

Glycogen storage disease type II (GSDII, Pompe's disease) is caused by an autosomal recessive inheritance of lysosomal alpha-glucosidase def iciency. 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 C16 34T transition resulting in the substitution of pro545 by leu. The mor e severely affected adolescent patient had this same mutant allele com bined with a 1 base pair deletion (Delta T525) in the second allele ca using premature termination at nucleotide positions 658 - 660. Both th ese mutations were introduced in wild-type alpha-glucosidase cDNA and expressed in COS-1 cells to analyse their effect. The Delta T525 mutat ion prohibits the formation of lysosomal cr-glucosidase completely. Th e pro545-->leu substitution is compatible with normal synthesis but ha mpers enzyme maturation and results in a 92% net loss of lysosomal alp ha-glucosidase activity. The patient with adult GSDII has, in accordan ce with the allelic constitution, a 2-fold higher residual activity th an the patient with juvenile GSDII. The Delta T525 deletion was detect ed in two other unrelated patients, and also the C1634T transition was encountered in two more Caucasian patients with GSDII.