The G6PC gene encodes glucose-6-phosphatase, an integral membrane enzyme of the endoplasmic reticulum. The enzyme is responsible for the breakdown of glucose-6-phosphate into glucose, and hence plays a key role in maintaining glucose homeostasis through the pathways of gluconeogenesis and glycogenolysis. The enzyme is also involved in cholesterol homeostasis and regulation of gene expression.
In the absence of the G6PC enzyme, glucose-6-phosphatase is instead converted to fat and glycogen which accumulates in the cells. This toxic accumulation causes tissue and organ damage and eventually results in Glycogen Storage Disease Ia (GSD1a), a disorder characterized by growth retardation, hepatomegaly, lactic acidosis and hypoglycemia.
The G6PC gene is located on the long arm of chromosome 17. It spans a length of 13.6 kb of DNA and its coding sequence is spread across 5 exons. The gene encodes a 40 kDa protein product consisting of 357 amino acids. An additional 20 kDa isoform of the G6PC gene exists due to alternative splicing. The gene is found to be overexpressed in the liver, kidney, intestines and gallbladder. At least 85 mutations in the G6PC gene have been associated with GSD1a. These are mainly missense mutations that affect the protein’s enzyme activity.
Monies et al. (2017) detailed the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, an 8-year-old female from a consanguineous family, presented with GSD type 1, bleeding tendency and hypoglycemia. Using a multigene panel for inborn errors of metabolism, she was found to have dual molecular diagnosis: a homozygous c.247C>T (p.R83C) variant in exon 2 of the G6PC gene and a homozygous c.266G>A (p.R89H) variant in exon 2 of the GAA gene. Dual molecular diagnoses were rarely detected and occurred in only 1.5% of the cohort.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing for 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism and other genetic disorders. Among the cohort in whom variants of uncertain significance were considered likely pathogenic, 1 patient was diagnosed with glycogen storage disease Ia. A homozygous missense transversion in G6PC (c.352G>C; p.Ala118Pro) was identified as the probable cause.
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