Submission Details

Glucose-6-phosphatase (G6Pase) is membrane protein of the endoplasmic reticulum that is composed of a catalytic subunit and transporters for Glucose-6-phosphate, inorganic phosphate, and glucose. The enzyme causes hydrolysis of glucose-6-phosphate (G6P) into glucose during the terminal steps of gluconeogenesis and glycogenolysis (Shieh et al. 2002; Udawat et al. 2019). Glycogen storage disease type Ia (GSD-Ia, MIM232200) also known as von Gierke disease, is caused by deleterious mutations in the G6PC1 gene. Patients with GSD-Ia experience growth retardation, hypoglycaemia during fasting, and increased serum levels of uric acid, triglycerides, and cholesterol (Wang et al. 2013). The G6PC1 gene is expressed in the liver, kidney, and intestine, and these are the only organs that release glucose into the blood circulation. G6Pasedeficiency also leads to the accumulation of glucose-6 phosphate (G6P), glycogen, and triglycerides in the liver and kidneys of patients. This results in marked hepatomegaly and nephromegaly.

In this curation, 21 variants (missense, nonsense, frameshift), reported in 15 probands in 10 publications (PMID:17607665, 11196115, 11058918, 32436859, 10234610, 10797430, 27139513, 35834487, 8739966, 27511118) are included. GSD-Ia is not more prevalent in any ethnic group, but mutations unique to Caucasian, oriental, and Jewish populations have been described. GSD-Ia patients have been seen to exhibit phenotypic heterogeneity. Among these variants, p.R170X (PMID: 10797430) has been functionally characterized and completely inactivates the G6PC enzyme. The variant p.R83C (PMID:10797430) is identified as the most prevalent mutation in Caucasian and Jewish GSD-Ia patients. In Chinese patients the most prevalent mutations are p.R83H (PMID:324685) and c.648G>T (PMID:10797430).

The experimental evidence that support gene-disease relation include biochemical function analysis, functional alteration and animal models (PMID: 12093795, 10738525,8640227, 33359667, 21109326). The study by Ghosh et al., (PMID:12093795), reported the crucial role of His176 in G6Pase catalysis where this His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate showing that substituting His176 with an Ala residue also completely abolished G6Pase activity, a feature in GSD Ia patients. Functional alteration study was carried out using the hGlc6Pase cDNA cloned in pSVK3 (expression plasmid) which were transfected into COS7 cells. Glc6Pase activity of hGlc6Pase after insertion of the fourpoint mutations which were previously identified in French patients, e.g. W77R, A124T, G184E and L211P were analyzed both in terms of maximal velocity (Vmax) and Glc6P affinity (Km), in comparison with Glc6Pase assayed in microsomes isolated from normal human liver and kidney. None of the four new hGlc6Pase mutants exhibited a Glc6Pase activity higher than that of untransfected COS-7 cells (PMID:107538525). In mouse model study by Mutel et al., G6pc- / mice which were generated by an inducible CRE (CRE ERT2) strategy, demonstrated hyperlipidemia, lactic acidosis, and uricemia, hepatomegaly and steatosis (PMID:21109326). Another mouse model study by Arnaoutova et al., (PMID: 33359667) CRISPR/Cas9-based technology to generate a G6pc-R83C mouse line homozygous for G6PC-p.R83C. It was seen that G6pc-R83C mice were devoid of hepatic and renal G6Pase-α activity and died prematurely, and manifested impaired glucose homeostasis and frequent hypoglycemic seizures, like the symptoms of the global G6pc−/− mice (Lei KJ, 1996)(PMID:8640227), essentially the same pathophysiology as human GSD-Ia patients.

In summary, G6PC1 is definitively associated with autosomal recessive glycogen storage disease Ia and has been repeatedly demonstrated in both the research and clinical diagnosis settings. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date [09/27/2024] (SOP Version 10).