Glycogen storage disease type 1a in Israel: Biochemical, clinical, and mutational studies

Abstract

Glycogen storage disease type 1a (von Gierke disease, GSD 1a) is caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) activity which catalyzes the final common step of glycogenolysis and gluconeogenesis. The recent cloning of the G6Pase cDNA and characterization of the human G6Pase gene enabled the characterization of the mutations causing GSD 1a. This, in turn, allows the introduction of a noninvasive DNA-based diagnosis that provides reliable carrier testing and prenatal diagnosis. In this study, we report the biochemical and clinical characteristics as well as mutational analyses of 12 Israeli GSD 1a patients of different families, who represent most GSD 1a patients in Israel. The mutations, G6Pase activity, and glycogen content of 7 of these patients were reported previously. The biochemical data and clinical findings of all patients were similar and compatible with those described in other reports. All 9 Jewish patients, as well as one Muslim Arab patient, presented the R83C mutation. Two Muslim Arab patients had the V166G mutation which was not found in other patients' populations. The V166G mutation, which was introduced into the G6Pase cDNA by site-directed mutagenesis following transient expression in COS-1 cells, was shown to cause complete inactivation of the G6Pase.The characterization of all GSD 1a mutations in the Israeli population lends itself to carrier testing in these families as well as to prenatal diagnosis, which was carried out in 2 families. Since all Ashkenazi Jewish patients harbor the same mutation, our study suggests that DNA-based diagnosis may be used as an initial diagnostic step in Ashkenazi Jews suspected of having GSD 1a, thereby avoiding liver biopsy. Am. J. Med. Genet. 72:286-290, 1997.

Asparagine-linked Oligosaccharides Are Localized to a Luminal Hydrophilic Loop in Human Glucose-6-Phosphatase

“…Asn 203 is located in a cytoplasmic loop and mutation (N203A) of this residue had no adverse effects on protein synthesis, as similar amount of G6Pase were synthesized by WT or the N203A construct. Moreover, the N203A mutant retained 37% of WT activity, whereas all mutations uncovered in the G6Pase gene of GSD-1a patients abolish or markedly reduce (retaining 18% or less of WT activity) G6Pase activity (7,14,15,23,24). This suggests that the structural requirement of the cytoplasmic loops is less stringent than other features of human G6Pase.…”

“…1). Twelve missense mutations and the codon deletion mutation (⌬F327) were further examined for G6Pase activity in transient expression assays (7,14,15,23,24). These include R83C and R83H, which altered Arg…”

Genetic heterogeneity of glycogen storage disease type Ia in France: A study of 48 patients

“…However, by contrast, some mutations may be predominant in particular populations: the 727 G>T mutation accounts for 88% of mutant allles in Japaneses patients (Kajihara et al, 1995), the R83C mutation accounts for 93% of mutant alleles in Jewish patients (Parvari et al, 1997). Thus, for a patient with GSD Ia, it is important, prior to molecular investigations to have a precise knowledge of geographical origins of both parents.…”

Glycogen storage disease type I: diagnosis and phenotype/genotype correlation

“…With respect to GSD Ia, most studies identified mutations on all alleles investigated [1,3,11,14,17,38,42,50,62]. In a few publications, however, mutations were not iden- Only found in a patient homozygous for M5R and heterozygous for R83C, the latter not being included in this table [54] c New mutations S13 tified on several alleles with the poorest mutation detection rate of only 75% reported by Hu¨ner et al [11].…”

“…In one of our laboratories, mutations were identified on all 98 G6PC alleles analyzed to date [48]. GSD Ia is a genetically heterogenous disorder with 76 different mutations detected so far among mostly compound heterozygous patients from a total of 424 different families combining our own and published data (Table 1) [1,3,8,11,14,15,16,17,19,23,24,26,33,35,38,39,41,42,45,48,50,51,53,61,62,63,64]. Taking all these patients together, there are no true common mutations and more than 50% appear to be private mutations.…”