Molecular Mechanisms of Glucose-6-Phosphate Isomerase Deficiency

Glucose-6-phosphate isomerase (GPI) catalyses the reversible conversion of glucose-6-phosphate to fructose-6-phosphate, a pivotal step in glycolysis. Inherited as an autosomal recessive trait, GPI deficiency is characterised primarily by chronic non-spherocytic haemolytic anaemia of variable severity and, in rare cases, by neuromuscular or cognitive manifestations. The GPI gene, spanning 18 exons on chromosome 19q13.1, harbours over 40 distinct pathogenic variants, including missense, nonsense and splice-site mutations. These alterations may impair catalytic efficiency, destabilise the dimeric enzyme or disrupt oligomerisation, leading to reduced erythrocyte energy supply, accumulation of glycolytic intermediates and enhanced oxidative stress. Beyond its metabolic role, GPI also functions extracellularly as a cytokine and neurotrophic factor, and deficiency may perturb these non-enzymatic actions. Genotype–phenotype correlations remain incomplete: residual enzyme activity, allelic combinations and modifying factors contribute to clinical heterogeneity. Current diagnosis relies on enzymatic assays and molecular sequencing, while management is largely supportive, encompassing transfusion, occasional splenectomy and genetic counselling. Elucidation of molecular defects is essential for accurate diagnosis, family planning and exploration of targeted therapies.

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Technical terms

Glycolysis: Metabolic pathway that converts glucose into pyruvate, producing ATP and NADH.

Autosomal recessive: Inheritance pattern requiring two mutated alleles for disease expression.

Haemolytic anaemia: Reduction in red blood cell count due to premature destruction of erythrocytes.

Exon: Coding segment of a gene that remains in mature mRNA after splicing.

Missense mutation: Single nucleotide change that replaces one amino acid with another in a protein.

Pre-mRNA splicing: Cellular process removing non-coding introns and joining exons to form mature mRNA.

Compound heterozygous: Presence of two different mutant alleles at a single gene locus, one on each chromosome.

References

1. Clinical and Molecular Spectrum of Glucose-6-Phosphate Isomerase Deficiency. Report of 12 New Cases. Frontiers in Physiology (2019).
2. The novel compound heterozygous variants identified in a Chinese family with glucose phosphate isomerase deficiency and pathogenicity analysis. BMC Medical Genomics (2023).
3. Hereditary nonspherocytic hemolytic anemia caused by glucose-6-phosphate isomerase (GPI) deficiency in a Chinese patient: a case report. BMC Pediatrics (2022).