Aberrant splicing at catalytic site as cause of infantile onset glycogen storage disease type II (GSDII): Molecular identification of a novel IVS9 (+2GT -> GC) in combination with rare IVS10 (+1GT -> CT)

Glycogen storage disease type II: (GSDII) results from deleterious mutation s in acid alpha -glucosidase gene. To date several mutant alleles have been studied including missense and nonsense mutations, insertions, small and l arge deletions as well as splice site mutations. Apart from IVS1 (-13 -->G) , 525delT, and Delta 18, the other mutations are rare and often unique to s ingle patients. Moreover, the molecular findings also observed in the diffe rent ethnic groups makes it difficult to attempt to correlate genotype and phenotype to explain the origin of clinical variability. Even though there are no conclusive genotype phenotype correlations, the in frame splice site mutations identified up until now have been found associated with the juve nile/adult onset of GSDII. In this study we describe a novel in frame splic ing defect, IVS9 (+2GT --> GC), identified in combination with the rare IVS 10 (+IGT --> CT) mutation in a patient with classic infantile GSDII disease . Because both mutations occur at the catalytic site region, it is likely t hat the alteration of both catalytic function and steric conformation of th e enzyme may be responsible for the most severe form of the disease. (C) 20 01 Wiley-Liss, Inc.