Heterogeneous mutations in the glucose-6-phosphatase gene in Japanese patients with glycogen storage disease type Ia

Glycogen storage disease type Ia (GSD-Ia) is an autosomal recessive disorde r of glycogen metabolism caused by glucose-6-phosphatase (G6Pase) deficienc y. It is characterized by short stature, hepatomegaly, hypoglycemia, hyperu ricemia, and lactic acidemia. Various mutations have been reported in the G 6Pase gene (G6PC), However, in Japanese patients, a g727t substitution was found to be the major cause of GSD-Ia, accounting for 20 of 22 mutant allel es [Kajihara et al,, 1995], and no other mutations have been found in this population. We analyzed four Japanese GSD-Ia patients and identified three other mutations in addition to the g727t, They included two missense mutati ons (R83H and P257L) and one nonsense mutation (R170X), Each of the three m utations exhibited markedly decreased G6Pase activity when expressed in COS 7 cells. A patient homozygous for R170X showed multiple episodes of profoun d hypoglycemia associated with convulsions, while P257L was associated with a mild clinical phenotype, The presence of R170X in three unrelated famili es may implicate that it is another important mutation in the etiology of G SD-Ia in Japanese patients. Thus, the detection of non-g727t mutations is a lso important in establishing the DNA-based diagnosis of GSD-Ia in this pop ulation. Am. J. Med, Genet, 92:90-94, 2000. (C) 2000 Wiley-Liss, Inc.