EXON REDEFINITION BY A POINT MUTATION WITHIN EXON-5 OF THE GLUCOSE-6-PHOSPHATASE GENE IS THE MAJOR CAUSE OF GLYCOGEN-STORAGE-DISEASE TYPE-1A IN JAPAN

Glycogen storage disease (GSD) type la (von Gierke disease) is an auto somal recessive disorder caused by a deficiency in microsomal glucose- 6-phosphatase (G6Pase). We have identified a novel mutation in the G6P ase gene of a individual with GSD type 1a. The cDNA from the patient's liver revealed a 91-nt deletion in exon 5. The genomic DNA from the p atient's white blood cells revealed no deletion or mutation at the spl icing junction of intron 4 and exon 5. The 3' splicing occurred 91 bp from the 5' site of exon 5 (at position 732 in the coding region), cau sing a substitution of a single nucleotide (G to T) at position 727 in the coding region. Further confirmation of the missplicing was obtain ed by transient expression of allelic minigene constructs into animal cells. Another eight unrelated families of nine Japanese patients were all found to have this mutation. This mutation is a new type of splic ing mutation in the G6Pase gene, and 91% of patients and carriers suff ering from GSD1a in Japan are detectable with this splicing mutation.