1. Functional characterization of the p.(Gln195His) or Tainan and novel p.(Ser184Cys) or Toluca glucose-6-phosphate dehydrogenase (G6PD) gene natural variants identified through Mexican newborn screening for glucose-6-phosphate dehydrogenase deficiency.
- Author
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Alcántara-Ortigoza MA, Hernández-Ochoa B, González-Del Angel A, Ibarra-González I, Belmont-Martínez L, Gómez-Manzo S, and Vela-Amieva M
- Subjects
- Humans, Male, Infant, Newborn, Glucosephosphate Dehydrogenase genetics, Glucosephosphate Dehydrogenase chemistry, Neonatal Screening, NADP, Mexico, Glucosephosphate Dehydrogenase Deficiency diagnosis, Glucosephosphate Dehydrogenase Deficiency genetics
- Abstract
Background: Newborn screening for glucose-6-phosphate dehydrogenase deficiency (G6PDd) was implemented in Mexico beginning in 2017. In a Mexican population, genotyping analysis of G6PD as a second-tier method identified a previously unreported missense variant, p.(Ser184Cys), which we propose to call "Toluca", and the extremely rare p.(Gln195His) or "Tainan" variant, which was previously described in the Taiwanese population as a Class II allele through in silico evaluations. Here, we sought to perform in vitro biochemical characterizations of the Toluca and Tainan G6PD natural variants and describe their associated phenotypes., Methods: The "Toluca" and "Tainan" variants were identified in three unrelated G6PDd newborn males, two of whom lacked evidence of acute hemolytic anemia (AHA) or neonatal hyperbilirubinemia (NHB). We constructed wild-type (WT), Tainan, and Toluca G6PD recombinant enzymes and performed in vitro assessments., Results: Both variants had diminished G6PD expression, decreased affinities for glucose-6-phosphate and NADP
+ substrates, significant decreases in catalytic efficiency (∼97 % with respect to WT-G6PD), and diminished thermostabilities that were partially rescued by NADP+ . In silico protein modeling predicted that the variants would have destabilizing effects on the protein tertiary structure, potentially reducing the enzyme half-lives and/or catalytic efficiencies., Conclusion: Our data suggest that G6PD "Tainan" and "Toluca" are potential Class II natural variants, which agrees with the absence of chronic nonspherocytic hemolytic anemia (CNSHA) in our patients. It remains to be determined whether these variants represent high-risk genetic factors for developing CNSHA, AHA, and/or NHB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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