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

G6PD deficiency results from mutations in the X-linked G6PD gene. More than 200 variants are associated with enzyme deficiency: each one of them may either cause predisposition to haemolytic anaemia triggered by exogenous agents (class B variants), or may cause a chronic haemolytic disorder (class A variants). Genotype-phenotype correlations are subtle. We report a rare G6PD variant, discovered in a baby presenting with severe jaundice and haemolytic anaemia since birth: the mutation of this class A variant was found to be p.(Arg454Pro). Two variants affecting the same codon were already known: G6PD Union, p.(Arg454Cys), and G6PD Andalus, p.(Arg454His). Both these class B variants and our class A variant exhibit severe G6PD deficiency. By molecular dynamics simulations, we performed a comparative analysis of the three mutants and of the wild-type G6PD. We found that the tetrameric structure of the enzyme is not perturbed in any of the variants; instead, loss of the positively charged Arg residue causes marked variant-specific rearrangement of hydrogen bonds, and it influences interactions with the substrates G6P and NADP. These findings explain severe deficiency of enzyme activity and may account for p.(Arg454Pro) expressing a more severe clinical phenotype.

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Publication Details

Journal
British Journal of Haematology
Published
2024-09-18
DOI
https://doi.org/10.1111/bjh.19775
Citations
2
Primary Topic
Neonatal Health and Biochemistry
Type
article
Field-Weighted Citation Impact
2.22
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article

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

Giorgia Prontera, Mariannita Gelsomino, Stefano Mastrangelo, Milena Tana et al.
2 citations
British Journal of Haematology
Neonatal Health and Biochemistry
2.22
article

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

Giorgia Prontera, Mariannita Gelsomino, Stefano Mastrangelo, Milena Tana, Lucio Luzzatto, Giovanni Vento, Carlo Camilloni, Martino Bolognesi, Antonio Ruggiero, Valentina Giorgio, Eloisa Tiberi, Angelo Minucci, Amit Kumawat, Simonetta Costa, Maria Elisabetta Onori, Alberto Romano, Maria De Bonis, Giuseppe Palumbo
article en
2 citations

Abstract

G6PD deficiency results from mutations in the X-linked G6PD gene. More than 200 variants are associated with enzyme deficiency: each one of them may either cause predisposition to haemolytic anaemia triggered by exogenous agents (class B variants), or may cause a chronic haemolytic disorder (class A variants). Genotype-phenotype correlations are subtle. We report a rare G6PD variant, discovered in a baby presenting with severe jaundice and haemolytic anaemia since birth: the mutation of this class A variant was found to be p.(Arg454Pro). Two variants affecting the same codon were already known: G6PD Union, p.(Arg454Cys), and G6PD Andalus, p.(Arg454His). Both these class B variants and our class A variant exhibit severe G6PD deficiency. By molecular dynamics simulations, we performed a comparative analysis of the three mutants and of the wild-type G6PD. We found that the tetrameric structure of the enzyme is not perturbed in any of the variants; instead, loss of the positively charged Arg residue causes marked variant-specific rearrangement of hydrogen bonds, and it influences interactions with the substrates G6P and NADP. These findings explain severe deficiency of enzyme activity and may account for p.(Arg454Pro) expressing a more severe clinical phenotype.

British Journal of HaematologyVol. 205(5)
Università Cattolica del Sacro Cuore (IT), Muhimbili University of Health and Allied Sciences (TZ), University of Milan (IT), Agostino Gemelli University Polyclinic (IT), Bambino Gesù Children's Hospital (IT), University of Florence (IT)
Openalex Percentile: Top 11%
Neonatal Health and Biochemistry
2.22
DOIOpen Access PDFOpenAlex
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