Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease

Deficiency of glycogen debranching enzyme (AGL) activity causes glycogen st orage disease type III (GSD-III). Generalized loss of AGL activity results in GSD-IIIa, and muscle-specific retention of AGL activity results in GSD-I IIb. To date, no common mutation has been described among GSD-III patients, except for three alleles; two linked specifically with GSD-IIIb, and the t hird found only in North African Jews with GSD-IIIa. Here we report two fre quent mutations, each of which was found in the homozygous state in multipl e patients, and each of which was associated with a subset of clinical phen otype in those patients with that mutation. A novel point mutation of a sin gle T deletion at cDNA position 3964 (3964delT) was first detected in an Af rican American patient, who has a severe phenotype and early onset of clini cal symptoms. The second mutation was an A to G transition at position -12 upstream of the 3' splice site of intron 32 (IVS32-12A > G). This lesion, p reviously implicated as a IIIb mutation in a Japanese patient, was identifi ed in a confirmed GSD-IIIa Caucasian patient presenting with mild clinical symptoms. These two mutations together account for more than 12% of the mol ecular defects in the GSD-III patients tested. Our molecular and clinical d ata suggest a genotype-phenotype correlation for each of these mutations. F urthermore, this current study, coupled with our previous reports, describe s the molecular tools necessary for the development of a DNA-based diagnost ic test for GSD-III, (C) 2000 Academic Press.