Molecular characterisation of GSD III subjects and identification of six novel mutations in AGL.

Deficiency of amylo-1,6-glucosidase, 4-alpha-glucanotransferase enzyme (AGL or glycogen debranching enzyme) is causative of Glycogen Storage Disease type III, a rare autosomal recessive disorder of glycogen metabolism. The disease has been demonstrated to show clinical and biochemical heterogeneity, reflecting the genotype-phenotype heterogeneity among different subjects. The aim of this study was the molecular characterisation of eight unrelated patients from an ethnically heterogeneous population (six Italians, one from India and another one from Tunisia). We describe six novel mutations responsible for the disease (C234R, R675W, 2547delG, T38A, W1327X, IVS6 +3 A>G) and the presence in two Italian subjects of a splice variant (IVS21(+1) G>A) already described elsewhere. This last one is confirmed to be the most frequent mutation among the Italian patients come to our observation, accounting for 28% of 21 patients. One subject was found to be a compound heterozygous. Our data confirm the substantial genetic heterogeneity of this disease. Consequently, the strategy of mutation finding based on screening of recurrent common mutations is limited, as far as regards Italian GSD III patients, to check for the presence of IVS21(+1) G>A.