Twenty-two novel mutations in the lysosomal ?-glucosidase gene (GAA) underscore the genotype-phenotype correlation in glycogen storage disease type II

Abstract

Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid alpha-glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid alpha-glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid alpha-glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice-site mutation was investigated by real-time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype-phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease.

Pompe disease diagnosis and management guideline

“…A small number of laboratories offer DNA diagnostic and/or prenatal diagnostic testing for Pompe disease (see www.genetests.org and http://biochemgen.ucsd.edu/). Some genotype:phenotype correlations have been observed 2,97. Some laboratories may only screen for common mutations rather than provide full gene sequencing.…”

Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease

“…5 So far, close to 300 genetic mutations responsible for Pompe disease have been reported. 1,[6][7][8] Among them there is a group of mutations that affects the post-translational processing and transport of the enzyme protein. As it is well known that the detrimental effect of most mutations in lysosomal diseases is on protein folding, giving rise to processing and transport defects, 9 it is necessary to elucidate the structural cause of processing and transport defects.…”

Silent exonic mutation in the acid-α-glycosidase gene that causes glycogen storage disease type II by affecting mRNA splicing

“…However, two other base changes (G to C and G to A) at the same position have been described previously. 10,11 Both of the c.546G4C and c.546G4A mutations did not lead to an amino-acid substitution, but seemed to modify the splice donor site of exon 2. A Spanish patient with the c.546G4C mutation presented with the adult form of this disease and had 21% residual enzyme activity in the fibroblasts.…”

“…12 The c.546G4A mutation was found in a British patient, in combination with the fully delirious c.525del mutation on the second allele. 11 The patient was diagnosed at the age of 68 years and had only 3% residual enzyme activity in the fibroblasts. The c.546G4T variation identified in this patient also seemed to diminish the potential of the splice donor site, as the splice-site prediction program indicated.…”