Glycogen storage disease type II: Genetic and biochemical analysis of novel mutations in infantile patients from Turkish ancestry

Glycogen Storage Disease type II (GSDII) is caused by the deficiency of lysosomal α‐glucosidase (acid maltase). This paper reports on the characterization of the molecular defects in 6 infantile patients from Turkish ancestry. Five of the 6 patients had reduced levels of the lysosomal α‐glucosidase precursor. Conversion to mature enzyme was impaired in all cases, and the lysosomal α‐glucosidase activity in all patients fibroblasts was less than 0.5% of control. DNA sequence analysis revealed 3 new mutations. One mutation, found in 3 patients in homozygous form, was a double insertion in exon 19 (2471AG→CAGG) leading to a frameshift after Pro 913. It is the first insertion mutation described in the lysosomal α‐glucosidase gene. Two patients were homozygous for missense mutations leading to the substitution of Ser to Pro at amino acid 566 (S566P) in one case and of Pro to Arg at amino acid 768 (P768R) in the other. One patient was found to have a Gly to Arg missense mutation at amino acid 643 (G643R), previously identified in an adult patient (Hermans et al., 1993), combined with a silent second allele. The latter 3 mutations were introduced in the wild type lysosomal α‐glucosidase cDNA and expressed in COS cells to analyze their effect. Precursor species of 110 kD were formed but the maturation was impaired. As a result there was an overall deficiency of catalytic activity, which is in accordance with the findings in the patients fibroblasts and with the clinical phenotype. Hum Mutat 11:209–215, 1998. © 1998 Wiley‐Liss, Inc.