HEPATIC AND NEUROMUSCULAR FORMS OF GLYCOGEN-STORAGE-DISEASE TYPE-IV CAUSED BY MUTATIONS IN THE SAME GLYCOGEN-BRANCHING ENZYME GENE

Glycogen storage disease type IV (GSD-IV) is an autosomal recessive di sease resulting from deficient glycogen-branching enzyme (GBE) activit y. The classic and most common form is progressive liver cirrhosis and failure Leading to either liver transplantation or death by 5 yr of a ge. However, the liver disease is not always progressive. In addition, a neuromuscular type of the disease has been reported. The molecular basis of GSD-TV is not known, nor is there a known reason for the clin ical variability. We studied the GBE gene in patients with various pre sentations of GSD-IV. Three point mutations in the GBE gene were found in two patients with the classical presentation: R515C, F257L, and R5 24X. Transient expression experiments showed that these mutations inac tivated GBE activity. Two point mutations, L224P and Y329S, were detec ted in two separate alleles of a patient with the nonprogressive hepat ic form. The L224P resulted in complete loss of CBE activity, whereas the Y329S resulted in loss of similar to 50% of GBE activity, The Y329 S allele was also detected in another patient with the nonprogressive form of GSD-IV but not in 35 unrelated controls or in patients with th e more severe forms of GSD-IV. A 210-bp deletion from nucleotide 873 t o 1082 of the GBE cDNA was detected in a patient with the fatal neonat al neuromuscular presentation. This deletion, representing the loss of one full exon, was caused by a 3' acceptor splicing site mutation tag to aa). The deletion abolished GBE activity. Our studies indicate tha t the three different forms of GSD-IV were caused by mutations in the same GBE gene. The data also suggest that the significant retention of GBE activity in the Y329S allele may be a reason for the mild disease . Further study of genotype/phenotype correlations may yield useful in formation in predicting the clinical outcomes.