Glycogen storage disease type Ia: Molecular diagnosis of 51 Japanese patients and characterization of splicing mutations by analysis of ectopically transcribed mRNA from lymphoblastoid cells
J. Akanuma et al., Glycogen storage disease type Ia: Molecular diagnosis of 51 Japanese patients and characterization of splicing mutations by analysis of ectopically transcribed mRNA from lymphoblastoid cells, AM J MED G, 91(2), 2000, pp. 107-112
Glycogen storage disease type Ia (GSD-Ia) is an autosomal recessive disorde
r of glycogen metabolism caused by a deficiency of glucose-6-phosphatase (G
6Pase) that is expressed in the liver, kidney, and intestinal mucosa. Clini
cal manifestations include short stature, hepatomegaly, hypoglycemia, hyper
uricemia, and lactic acidemia. To elucidate a spectrum of the G6Pase gene m
utations and their frequencies, we analyzed mutations in 51 unrelated Japan
ese patients with GSD-Ia. The most prevalent mutation was g727t, accounting
for 88 of 102 mutant alleles examined, followed by R170X mutation, which a
ccounted for 6 mutant alleles, and R83H mutation which was observed in 3 mu
tant alleles. In addition, 3 different, novel mutations, IVS1-1g<a, Gly122-
to-Asp (G122D) and His179-to-Pro (H179P), were identified. We were able to
detect "ectopically" transcribed G6Pase-mRNA in Epstein-Barr virus-transfor
med lymphoblastoid cells and observed aberrant mRNA splicing associated wit
h the g727t and IVS1-1g<a mutations. To our knowledge, this is the first re
port that ectopic expression can be utilized for the characterization of GS
D-Ia mutations. Our findings suggest that a screening for the g727t, R170X,
and R83H mutations by simple DNA-based diagnostic methods can detect 95% o
f the G6Pase mutant alleles in Japanese patients with GSD-Ia, and remaining
mutations can be identified and characterized by the direct sequencing of
genomic DNA and/or the analysis of ectopically expressed mRNA. The noninvas
ive molecular diagnosis for GSD-Ia may ultimately replace the conventional
means of enzymatic diagnosis that requires liver biopsy. (C) 2000 Wiley-Lis
s, Inc.