GLYCOGEN-STORAGE-DISEASE TYPE-II - IDENTIFICATION OF 4 NOVEL MISSENSEMUTATIONS (D645N, G648S, R672W, R672Q) AND 2 INSERTIONS DELETIONS IN THE ACID ALPHA-GLUCOSIDASE LOCUS OF PATIENTS OF DIFFERING PHENOTYPE/

Glycogen storage disease type II (GSDII), an autosomal recessive myopa thic disorder, results from deficiency of lysosomal acid alpha-glucosi dase. We searched for mutations in an evolutionarily conserved region in 54 patients of differing phenotype, Four novel mutations (D645N, G4 48S, R672W, and R672Q) and a previously described mutation (C647W) wer e identified in five patients and their deleterious effect on enzyme e xpression demonstrated in vitro. Two novel frameshifting insertions/de letions (Delta nt766-785/insC and +insG@nt2243) were identified in two patients with exon 14 mutations, The remaining three patients were ei ther homozygous for their mutations (D645N/D645 and C647W/C647W) or ca rried a previously described leaky splice site mutation (IVS1 -13T-->G ). For all patients ''in vivo'' enzyme activity was consistent with cl inical phenotype, Agreement of genotype with phenotype and in vitro ve rsus in vivo enzyme was seen in three patients (two infantile patients carrying C647W/C647W and D645N/+insG@nt2243 and an adult patient hete roallelic for G648S/IVS1 -13T-->G). Relative discordance was found in a juvenile patient homozygous for the non-expressing R672Q and an adul t patient heterozygous for the minimally expressing R672W and Delta nt 766-785/+insC. Possible explanations include differences in in vitro a ssays vs in vivo enzyme activity, tissue specific expression with dimi nished enzyme expression/stability in fibroblasts vs muscle, somatic m osaicism, and modifying genes. (C) 1998 Academic Press.