ABERRANT SPLICING IN ADULT-ONSET GLYCOGEN-STORAGE-DISEASE TYPE-II (GSDII) - MOLECULAR-IDENTIFICATION OF AN IVS1 (-13T-]G) MUTATION IN A MAJORITY OF PATIENTS AND A NOVEL IVS10 (-]CT) MUTATION(1GT)

Two newly identified splice site mutations (IVS1 - 13'b --> G and IVS1 0 + 1GT --> CT) were found in a patient with adult onset of the autoso mal recessive disorder glycogen storage disease type II (GSDII). The I VS1 - 13T --> G transversion in the acceptor splice site was found on one allele in over two thirds of adult onset GSDII patients studied (2 8/41), but was not seen in 58 normal or 12 infantile onset GSDII chrom osomes. Molecular analysis of cDNA from the index patient and four add itional, ethnically different, individuals carrying the IVS1 - 13T --> G transversion showed splicing out of the first coding exon as well a s rare utilization of a cryptic splice site in the exon. An IVS10 + 1G T --> CT transversion, unique to the index patient, was detected on th e second chromosome, The IVS10 + 1GT --> CT results in splicing out of exon 10 including part of the enzyme catalytic site. Additionally, a large deletion encompassing exon 18, previously described in four unre lated patients, was also detected in three unrelated adult GSDII patie nts, two of whom carried the IVS1 - 13T --> G transversion. The freque ncy of the IVS1 splice site mutation suggests that detection of this m utation could potentially aid in the diagnosis of the phenotypically v ariable syndrome of adult onset GSDII. The finding that the - 13T --> G mutation is a very common mutation in adult onset GSDII patients of varying ethnic and racial backgrounds, suggests that it is either an a ncient mutation or confers a selective advantage, Although to our know ledge these are the first splice site mutations to be reported for GSD II, additional splice site mutations are likely and could provide the basis for later onset disease in GSDII.