Pathogenic G6PD variants: Different clinical pictures arise from different missense mutations in the same codon

Area of Science:

• Genetics
• Biochemistry
• Molecular Biology

Background:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency arises from mutations in the G6PD gene.
• Over 200 variants exist, categorized by severity (Class A: chronic hemolytic disorder, Class B: triggered hemolytic anemia).
• Genotype-phenotype correlations in G6PD deficiency are complex.

Purpose of the Study:

• To characterize a rare, severe Class A G6PD variant, p.(Arg454Pro), identified in a neonate with severe hemolytic anemia.
• To compare the structural and functional effects of p.(Arg454Pro) with known Class B variants (p.(Arg454Cys) and p.(Arg454His)) at the same codon.
• To elucidate the molecular mechanisms underlying the severe enzyme deficiency and clinical phenotype.

Main Methods:

• Identification and sequencing of a novel G6PD variant (p.(Arg454Pro)).
• Comparative analysis of wild-type and mutant G6PD enzymes using molecular dynamics simulations.
• Assessment of structural integrity, hydrogen bonding, and substrate interactions (G6P, NADP).

Main Results:

• The p.(Arg454Pro) variant causes severe G6PD deficiency, presenting with neonatal jaundice and hemolytic anemia.
• Molecular dynamics simulations showed no perturbation of the enzyme's tetrameric structure.
• Loss of the Arg454 residue induced variant-specific hydrogen bond rearrangements and altered substrate interactions, explaining the severe enzyme deficiency.

Conclusions:

• The p.(Arg454Pro) variant represents a rare Class A G6PD deficiency with a severe clinical phenotype.
• Structural analysis reveals that altered hydrogen bonding and substrate interactions, not tetramer instability, are key to the severe enzyme deficiency.
• These findings provide molecular insights into genotype-phenotype correlations for G6PD deficiency variants.