Alternative titles; symbols
HGNC Approved Gene Symbol: G6PC1
SNOMEDCT: 444707001;
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38) : 17:42,900,799-42,914,438 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | Glycogen storage disease Ia | 232200 | Autosomal recessive | 3 |
Glucose-6-phosphatase (G6PC; EC 3.1.3.9), the key enzyme in the homeostasis regulation of blood glucose concentrations, catalyzes the terminal step in gluconeogenesis and glycogenolysis (summary by Lei et al., 1993).
Lei et al. (1993) cloned human G6PC from a liver cDNA library. G6PC encodes a predicted 357-amino acid protein with an endoplasmic reticulum (ER) retention signal and 6 putative membrane-spanning segments. The expressed protein is indistinguishable from human microsomal G6Pase. Lei et al. (1993) stated that the gene had previously eluded molecular characterization primarily because of its tight association with the ER and nuclear membranes.
Shelly et al. (1993) isolated cDNAs encoding G6Pase by taking advantage of an albino deletion mutant mouse that is known to express markedly reduced levels of G6Pase activity. The primary defect of this mutant mouse is a loss of the fumarylacetoacetate hydrolase gene (FAH; 613871) located near the albino locus on chromosome 7. Fumarylacetoacetate hydrolase (or fumarylacetoacetase) is the final enzyme in the tyrosine degradation pathway, and a deficiency of this enzyme leads to the accumulation of toxic tyrosine metabolites, resulting in reduced expression of a group of liver-specific proteins, including G6Pase. Newborn homozygous deletion mice develop hypoglycemia shortly after birth, correlating with undetectable levels of G6Pase activity. Shelly et al. (1993) isolated a full-length cDNA encoding murine liver microsomal G6Pase by screening a normal mouse liver cDNA library differentially with probes representing mRNA populations from the normal and the albino deletion mutant mouse.
Lei et al. (1993) determined that the G6PC gene contains 5 exons and spans approximately 12.5 kb.
Shelly et al. (1993) showed that the mouse G6Pase transcription unit spans approximately 10 kb and contains 5 exons.
By analysis of somatic cell hybrids, Lei et al. (1994) mapped the G6PC gene to chromosome 17.
In the course of constructing a transcription map of approximately 600 kb of genomic DNA surrounding the BRCA1 gene (113705), Brody et al. (1995) identified the G6PC gene, thus regionalizing its assignment to 17q21.
In 2 patients with glycogen storage disease Ia (GSD1A; 232200), Lei et al. (1993) identified homozygous and compound heterozygous mutations, respectively, in the G6PC gene (613742.0001-613742.0003).
Lei et al. (1995) used SSCP analysis and DNA sequencing to characterize the G6PC gene of 70 unrelated patients with enzymatically confirmed diagnosis of type Ia GSD and detected mutations in all except 17 alleles (88%). They uncovered 16 mutations that were shown by expression to abolish or greatly reduce G6Pase activity and that, therefore, were responsible for the clinical disorder. R83C (613742.0002) and Q347X (613742.0004) were the most prevalent mutations found in Caucasians; 130X (613742.0001) and R83C were most prevalent in Hispanics; R83H was most prevalent in Chinese. The Q347X mutation was identified only in Caucasians, and the 130X mutation was identified only in Hispanic patients.
Kajihara et al. (1995) identified a splice mutation in exon 5 (727G-T) of the G6PC cDNA from the liver of a Japanese patient with GSD type Ia (613742.0005). Another 8 unrelated Japanese families with a total of 9 affected individuals were found to have the same mutation, thus representing 91% of patients and carriers of GSD Ia in Japan.
Chevalier-Porst et al. (1996) sequenced both alleles of 24 French GSD type Ia patients; 14 different mutations were found, allowing the identification of complete genotypes for all the patients. These included 9 new mutations. Five mutations, Q347X, R83C, D38V (613742.0006), G188R (613742.0012), and 158Cdel, accounted for 75% of the mutated alleles.
Parvari et al. (1997) reported the biochemical and clinical characteristics as well as mutation analyses of 12 Israeli GSD Ia patients of different families, who represent most of the GSD Ia patients in Israel. All 9 Jewish patients, as well as a Muslim Arab patient, were found to have the R83C mutation (613742.0002). Two Muslim Arab patients had the val166-to-gly (V166G) mutation (613742.0014), which had not been found in other populations.
Akanuma et al. (2000) identified G6PC mutations in all alleles from 51 unrelated Japanese patients with GSD Ia. A total of 7 mutations were identified, including 3 novel mutations. The most prevalent mutation, 727G-T, accounting for 88 of 102 mutant alleles, creates an aberrant 3-prime splice site within exon 5. The authors demonstrated that ectopically transcribed G6Pase mRNA can be detected in lymphoblastoid cells and may be used for the characterization of mutations that affect mRNA splicing. They concluded that noninvasive molecular diagnosis may ultimately replace the conventional method of enzymatic diagnosis that requires liver biopsy in Japanese patients.
Stroppiano et al. (1999) analyzed the G6Pase gene in 53 unrelated Italian patients and identified 88 mutant alleles (82.6%) with 18 (17.4%) remaining unidentified. The most prevalent mutation was R83C (46.2%), followed by Q347X (20.7%); 3 other mutations (R295C, D38V, and G270V) accounted for 5.6% of disease alleles. The authors suggested that noninvasive screening could be used in Italian patients clinically suspected of having GSD Ia, particularly in those from Sicily, where the R83C mutation was present in 80% of mutant alleles. In all of 13 unrelated Korean patients with GSD Ia, Ki et al. (2004) identified mutant alleles of the G6PC gene. Three known mutations and 2 novel mutations were identified. The most frequent mutant allele was 727G-T, present in 21 of 26 alleles (81%), which was slightly lower than that in Japanese, where it was present in 86 alleles (92%), but much higher than that in Taiwan Chinese (present in 44.4% of alleles).
In a patient with glycogen storage disease Ia (GSD1A; 232200), Lei et al. (1993) found a 2-bp insertion at nucleotide 459 (TAins459) in exon 3 of the G6PC gene. The insertion caused a frameshift with generation of a stop codon at nucleotides 467-469. The predicted gene product was a severely truncated protein of 129 amino acids. The patient was homozygous for the TA insertion and the mother, the only parent available, was heterozygous. Lei et al. (1995) referred to this mutation as 130X referring to the number of the stop codon that was generated by the frameshift. The 130X mutation had been identified only in Hispanic patients.
Lei et al. (1993) concluded that a patient with type Ia glycogen storage disease (GSD1A; 232200) was a compound heterozygote for 2 different G6PC mutations: arg83-to-cys (R83C) and arg295-to-cys (R295C; 613742.0003), located in exons 2 and 5, respectively. The exon 5 mutation came from the father and the exon 2 mutation from the mother. Both mutations were thought to involve a CpG doublet. Lei et al. (1994) demonstrated that the R83C mutant has no detectable phosphohydrolase activity.
In a patient originally reported by Burchell and Waddell (1990) as having a novel form of type I glycogen storage disease due to a defect in the 21-kD stabilizing protein SP, Lei et al. (1995) demonstrated that in fact there was an R83C mutation in exon 2 of the G6PC gene. They found the same mutation in both homozygous and heterozygous form in patients with standard GSD type Ia.
Qu et al. (1996) performed prenatal diagnosis by chorionic villus sampling in an Ashkenazi Jewish family in which a previous child was homoallelic and both parents were heterozygous for the R83C mutation. Molecular analysis showed that the fetus was not affected.
Parvari et al. (1997) found that the R83C mutation was present in all Ashkenazi Jewish patients studied in Israel, suggesting that DNA-based diagnosis may be used as an initial diagnostic step in this population, thus avoiding liver biopsy.
Ekstein et al. (2004) tested 20,719 Ashkenazi Jewish subjects for the R83C mutation and identified 290 carriers, giving a carrier frequency of 0.014. The authors noted that this carrier frequency translates into a predicted disease prevalence of 1 in 20,000, 5 times higher than that for the general Caucasian population, confirming a founder effect and elevated frequency of type Ia glycogen storage disease in the Ashkenazi population. They also tested 4,290 Ashkenazi subjects for the Q347X (613742.0004) mutation and found no carriers. Of 30 Ashkenazi Jewish patients with type Ia glycogen storage disease, all were homozygous for the R83C mutation. Ekstein et al. (2004) concluded that R83C is the only prevalent mutation for this disease in the Ashkenazi population.
For discussion of the arg295-to-cys (R295C) mutation in the GSD1A gene that was found in compound heterozygous state in a patient with glycogen storage disease Ia (GSD1A; 232200) by Lei et al. (1993), see 613742.0002.
In a patient with glycogen storage disease Ia (GSD1A; 232200), Lei et al. (1994) demonstrated compound heterozygosity for an arg83-to-cys mutation (613742.0002) in exon 2 and a gln347-to-ter mutation in exon 5. The latter mutation was detected in homozygous form in 2 sibs of an unrelated family. The predicted Q347X mutant G6Pase is a truncated protein of 346 amino acids, 11 amino acids shorter than the wildtype G6Pase. Site-directed mutagenesis and transient expression assays demonstrated that the mutant protein is devoid of G6Pase activity.
In a 26-year-old man with glycogen storage disease Ia (GSD1A; 232200) and in 9 other Japanese patients from 8 unrelated families, Kajihara et al. (1995) identified a splicing mutation in the G6PC gene. The first patient was the progeny of first-cousin parents and had a history of hepatomegaly and hypoglycemia since childhood. The diagnosis of GSD Ia was based on the findings of hypoglycemia, hypertriglyceridemia, hyperuricemia and liver biopsy abnormalities. Residual G6Pase activity in the liver was 18% of normal in both fresh and previously frozen liver biopsy specimens. A younger brother was also affected. The cDNA prepared from the patient's liver had a deletion of 91 nucleotides with no normal-sized cDNA. The mutation resulted in a G6Pase polypeptide 146 amino acids shorter at the carboxy-terminal portion than the normal gene product of 357 residues. It was thought that the 18% of normal activity reflected nonspecific phosphatase activity since the G6Pase activity was low or not detectable in several unrelated GSD Ia patients homozygous for this mutation. Analysis of mutant genomic DNA demonstrated a G-to-T transversion at nucleotide 727 of their G6PC sequence. Although the patient's splice site in intron 4 and exon 5 had a normal consensus sequence, normal splicing did not occur. It is thought that the single base substitution, located far from the splice junction, altered the splice site. Kajihara et al. (1995) cited data indicating that 11% of aberrant splice mutations represent the creation of new splice sites with no alteration in the authentic splice site sequences. Nakai and Sakamoto (1994) found that new 5-prime and 3-prime sites were created only in the upstream region of the authentic 5-prime and 3-prime splice sites. However, this characteristically Japanese GSD Ia mutation is an exception; a new 3-prime site occurred in the downstream region of a normal splice site.
Akanuma et al. (2000) found that the most prevalent mutation in a study of 51 unrelated Japanese patients with GSD Ia was 727G-T, accounting for 88 of 102 mutant alleles.
In 4 unrelated French patients with glycogen storage disease Ia (GSD1A; 232200), Chevalier-Porst et al. (1996) found compound heterozygosity for a D38V missense mutation in the G6PC gene. This resulted from an A-to-T transversion of nucleotide 192 in exon 1. The mutation was predicted to change an acidic amino acid (aspartic acid) to a nonpolar hydrophobic amino acid (valine) in the middle of the first predicted transmembrane spanning domain.
In a French patient with glycogen storage disease Ia (GSD1A; 232200), Chevalier-Porst et al. (1996) found compound heterozygosity for a W77R missense mutation in the G6PC gene. The mutation changed a nonpolar hydrophobic amino acid (tryptophan) to a basic one (arginine). The amino acid substitution resulted from a T-to-C transition of nucleotide 308 in exon 1.
In a French patient with glycogen storage disease Ia (GSD1A; 232200), Chevalier-Porst et al. (1996) found an A-to-G transition at position +4 of the 5-prime donor splice site of intron 1 of the G6PC gene. The patient was compound heterozygous for this mutation and for the G188R mutation (613742.0012).
In a French patient with glycogen storage disease Ia (GSD1A; 232200), Chevalier-Porst et al. (1996) found a G-to-A transition at nucleotide 407 in exon 2 of the G6PC gene, resulting in an E110K missense mutation in the G6PC gene. The mutation changed an acidic amino acid (glutamic acid) to a basic amino acid (lysine). The mutation was present in compound heterozygous state.
In a French patient with glycogen storage disease Ia (GSD1A; 232200), Chevalier-Porst et al. (1996) identified a G-to-A transition at nucleotide 449 in exon 3 of the G6PC gene, which changed a nonpolar amino acid (alanine-124) to a polar one (threonine). This mutation, inherited from the mother, was associated with the Q347X mutation (613742.0004) in 2 sibs with GSD Ia.
In a French patient with glycogen storage disease Ia (GSD1A; 232200), Chevalier-Porst et al. (1996) found a G-to-A transition at nucleotide 630 of the G6PC gene, changing a nonpolar hydrophobic amino acid (glycine-184) to an acidic one (glutamic acid). The G184E mutation is located in the putative cytoplasmic domain of the enzyme. The mutation was present in homozygous state in a family with no known consanguinity.
In 3 unrelated French patients with glycogen storage disease Ia (GSD1A; 232200), Chevalier-Porst et al. (1996) found compound heterozygosity for a G-to-C transversion at nucleotide 641 of the G6PC gene, resulting in change of a nonpolar hydrophobic amino acid (glycine-188) to a basic one (arginine). This mutation, like G184E (613742.0011), is located in the putative cytoplasmic domain of the enzyme.
Weston et al. (2000) identified a 5-month-old girl with hypoglycemia, hepatomegaly, and lactic acidemia who was diagnosed with GSD Ia. She also developed neutropenia, neutrophil dysfunction, and recurrent infections characteristic of GSD Ib, but was found to be homozygous for the G188R mutation of the G6PC gene. No mutations in the G6PC translocase gene were identified. Weston et al. (2000) subsequently identified a sib of this proband and 2 unrelated patients with similar genotype-phenotype characteristics. They concluded that the unusual association of neutrophil abnormalities in patients with homozygous G188R mutations in the G6PC gene supports the modified translocase/catalytic unit model.
In 2 sibs with glycogen storage disease Ia (GSD1A; 232200), Lee et al. (1996) found compound heterozygosity for an R83C substitution in exon 2 (613742.0002) and an ile341-to-asp substitution in exon 5 of the G6PC gene. The nucleotide substitutions were a G-to-A transition at base position 327 in exon 2 and a T-to-A transversion at base position 1101 in exon 5. The father was heterozygous for the exon 2 mutation, and the mother was heterozygous for the exon 5 mutation.
In 2 Muslim Arab patients in Israel with glycogen storage disease Ia (GSD1A; 232200), Parvari et al. (1997) identified a homozygous 576T-G transversion in the G6PC gene, resulting in a val166-to-gly (V166G) missense mutation.
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