1. Pathogenic G6PD variants: Different clinical pictures arise from different missense mutations in the same codon
- Author
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Costa, Simonetta, Minucci, Angelo, Kumawat, A., Debonis, M., Prontera, G., Gelsomino, M., Tana, Milena, Tiberi, Eloisa, Romano, A., Ruggiero, Antonio, Mastrangelo, Stefano, Palumbo, Giulia, Giorgio, Valentina, Onori, Maria Elisabetta, Bolognesi, M., Camilloni, C., Luzzatto, L., Vento, Giovanni, Costa S., Minucci A., Tana M., Tiberi E., Ruggiero A. (ORCID:0000-0002-6052-3511), Mastrangelo S. (ORCID:0000-0002-3305-6014), Palumbo G., Giorgio V., Onori M. E., Vento G. (ORCID:0000-0002-8132-5127), Costa, Simonetta, Minucci, Angelo, Kumawat, A., Debonis, M., Prontera, G., Gelsomino, M., Tana, Milena, Tiberi, Eloisa, Romano, A., Ruggiero, Antonio, Mastrangelo, Stefano, Palumbo, Giulia, Giorgio, Valentina, Onori, Maria Elisabetta, Bolognesi, M., Camilloni, C., Luzzatto, L., Vento, Giovanni, Costa S., Minucci A., Tana M., Tiberi E., Ruggiero A. (ORCID:0000-0002-6052-3511), Mastrangelo S. (ORCID:0000-0002-3305-6014), Palumbo G., Giorgio V., Onori M. E., and Vento G. (ORCID:0000-0002-8132-5127)
- 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.
- Published
- 2024