Molecular Heterogeneity of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency in the Portuguese Population


  • Licínio Manco Centro de Investigação em Antropologia e Saúde. Universidade de Coimbra. Coimbra. Departamento de Ciências da Vida. Universidade de Coimbra. Coimbra.
  • Celeste Bento Centro de Investigação em Antropologia e Saúde. Universidade de Coimbra. Coimbra. Serviço de Hematologia Clínica. Centro Hospitalar e Universitário de Coimbra. Coimbra.
  • Luís Relvas Serviço de Hematologia Clínica. Centro Hospitalar e Universitário de Coimbra. Coimbra.
  • Tabita Maia Serviço de Hematologia Clínica. Centro Hospitalar e Universitário de Coimbra. Coimbra.
  • Maria Letícia Ribeiro Centro de Investigação em Antropologia e Saúde. Universidade de Coimbra. Coimbra.



Anemia, Hemolytic, Glucosephosphate Dehydrogenase Deficiency/epidemiology, Mutation, Portugal


Introduction: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme defect in the world, affecting more than 500 million people. In Portugal, the average frequency of G6PD deficiency in males was estimated at about 0.5% and since the year 2000 several G6PD-deficient alleles have been identified. The main goal of this study was to improve the knowledge on the molecular heterogeneity of G6PD deficiency in the Portuguese population.
Material and Methods: A retrospective analysis of the mutational profile of 138 unrelated Portuguese individuals (101 males; 37 females), with no known sub-Saharan ancestry, who had been diagnosed with G6PD deficiency between 1994 and 2020 at the Molecular Hematology Unit of Centro Hospitalar e Universitário de Coimbra. The molecular study was done by direct Sanger sequencing or PCR-RFLP analysis.
Results: Twenty-one different pathogenic mutations were found. Among them, 20 were missense, causing the amino acid change, and one was an in-frame deletion in exon 10. The three most frequent mutations belong to the G6PD c.376A>G African background haplotype, namely the G6PD variants: A- (c.202G>A; p.68Val>Met) (58.6%), Betica (c.968T>C; p.323Leu>Pro) (12.1%) and Santamaria (c.542A>T; p.181Asp>Val) (4.3%).
Conclusion: There is a wide molecular heterogeneity of G6PD deficiency in the Portuguese population.


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Luzzatto L, Ally M, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Blood. 2020;136:1225-40.

Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells Mol Dis. 2009;42:267-78.

Beutler E. G6PD deficiency. Blood. 1994;84:3613-36.

Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371:64-74.

Mason PJ, Bautista JM, Gilsanz F. G6PD deficiency: the genotypephenotype association. Blood Rev. 2007;21:267-83.

Beutler E, Duparc S; G6PD Deficiency Working Group. Glucose-6-phosphate dehydrogenase deficiency and antimalarial drug development. Am J Trop Med Hyg. 2007;77:779-89.

Luzzatto L, Nannelli C, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Hematol Oncol Clin North Am. 2016;30:373-93.

Belfield KD, Tichy EM. Review and drug therapy implications of glucose-6-phosphate dehydrogenase deficiency. Am J Health Syst Pharm. 2018;75:97-104.

Chen EY, Zollo M, Mazzarella R, Ciccodicola A, Chen CN, Zuo L, et al. Long-range sequence analysis in Xq28: thirteen known and six candidate genes in 219.4 kb of high GC DNA between the RCP/GCP and G6PD loci. Hum Mol Genet. 1996;5:659-68.

Persico MG, Viglietto G, Martini G, Toniolo D, Paonessa G, Moscatelli C, et al. Isolation of human glucose-6-phosphate dehydrogenase (G6PD) cDNA clones: primary structure of the protein and unusual 5’ non-coding region. Nucleic Acids Res. 1986;14:2511-22.

Minucci A, Moradkhani K, Hwang MJ, Zuppi C, Giardina B, Capoluongo E. Glucose-6-phosphate dehydrogenase (G6PD) mutations database: review of the “old” and update of the new mutations. Blood Cells Mol Dis. 2012;48:154-65.

Gómez-Manzo S, Marcial-Quino J, Vanoye-Carlo A, Serrano-Posada H, Ortega-Cuellar D, González-Valdez A, et al. Glucose-6-phosphate dehydrogenase: update and analysis of new mutations around the world. Int J Mol Sci. 2016;17:2069.

Martins MC, Olim G, Melo J, Magalhães HA, Rodrigues MO. Hereditary anaemias in Portugal: epidemiology, public health significance, and control. J Med Genet. 1993;30:235-9.

Rodrigues MO, Freire AP, Martins G, Pereira J, Martins MD, Monteiro C. Glucose-6-phosphate dehydrogenase deficiency in Portugal: biochemical and mutational profiles, heterogeneity, and haplotype association. Blood Cells Mol Dis. 2002;28:249-59.

Manco L, Gonçalves P, Antunes P, Maduro F, Abade A, Ribeiro ML. Mutations and haplotype diversity in 70 Portuguese G6PD-deficient individuals: an overview on the origin and evolution of mutated alleles. Haematologica. 2007;92:1713-4.

Manco L, Pereira J, Relvas L, Rebelo U, Crisóstomo AI, Bento C, et al. Chronic hemolytic anemia is associated with a new glucose-6-phosphate dehydrogenase in-frame deletion in an older woman. Blood Cells Mol Dis. 2011;46:288-93.

Beutler E, Blume KG, Kaplan JC, Löhr GW, Ramot B, Valentine WN. International Committee for Standardization in Haematology: recommended methods for red-cell enzyme analysis. Br J Haematol. 1977;35:331-40.

Beutler E, Kuhl W, Vives-Corrons JL, Prchal JT. Molecular heterogeneity of glucose-6-phosphate dehydrogenase A-. Blood. 1989;74:2550-5.

Vulliamy TJ, Rovira A, Yusoff N, Colomer D, Luzzatto L, Corrons JL. Independent origin of single and double mutations in the human glucose-6-phosphate dehydrogenase gene. Hum Mut. 1996;8:311-8.

Vulliamy TJ, Othman A, Town M, Nathwani A, Falusi AG, Mason PJ, et al. Polymorphic sites in the African population detected by sequence analysis of the glucose-6-phosphate dehydrogenase gene outline the evolution of the variants A and A-. Proc Natl Acad Sci U S A. 1991;88:8568-71.

Beutler E, Kuhl W, Sáenz GF, Rodríguez W. Mutation analysis of glucose-6-phosphate dehydrogenase (G6PD) variants in Costa Rica. Hum Genet. 1991;87:462-4.

May J, Meyer CG, Grossterlinden L, Ademowo OG, Mockenhaupt FP, Olumese PE, et al. Red cell glucose-6-phosphate dehydrogenase status and pyruvate kinase activity in a Nigerian population. Trop Med Int Health. 2000;5:119-23.

De Araujo C, Migot-Nabias F, Guitard J, Pelleau S, Vulliamy T, Ducrocq R. The role of the G6PD AEth376G/968C allele in glucose-6-phosphate dehydrogenase deficiency in the seerer population of Senegal. Haematologica. 2006;91:262-3.

Manco L, Botigué LR, Ribeiro ML, Abade A. G6PD deficient alleles and haplotype analysis of human G6PD locus in São Tomé e Príncipe (West Africa). Hum Biol. 2007;79:679-86.

Hung NM, Eto H, Mita T, Tsukahara T, Hombhanje FW, Hwaihwanje I, et al. Glucose-6-phosphate dehydrogenase (G6PD) variants in East Sepik Province of Papua New Guinea: G6PD Jammu, G6PD Vanua Lava, and a novel variant (G6PD Dagua). Trop Med Health. 2008;36:163-9.

Corcoran CM, Calabrò V, Tamagnini G, Town M, Haidar B, Vulliamy TJ, et al. Molecular heterogeneity underlying the G6PD Mediterranean phenotype. Hum Genet. 1992;88:688-90.

Costa E, Cabeda JM, Vieira E, Pinto R, Pereira SA, Ferraz L, et al. Glucose-6-phosphate dehydrogenase aveiro: a de novo mutation associated with chronic nonspherocytic hemolytic anemia. Blood. 2000;95:1499-501.

Menziletoglu Yildiz S, Yuzbasioglu Ariyurek S, Tahiroglu M, Aksoy K. Detection of 1311 polymorphism in the glucose-6-phosphate dehydrogenase gene by microarray technique. Arch Med Sci. 2011;7:586-91.

Benmansour I, Moradkhani K, Moumni I, Wajcman H, Hafsia R, Ghanem A, et al. Two new class III G6PD variants [G6PD Tunis (c.920A>C: p.307Gln>Pro) and G6PD Nefza (c.968T>C: p.323 Leu>Pro)] and overview of the spectrum of mutations in Tunisia. Blood Cells Mol Dis. 2013;50:110-4.

Hu R, Lin M, Ye J, Zheng BP, Jiang LX, Zhu JJ, et al. Molecular epidemiological investigation of G6PD deficiency by a gene chip among Chinese Hakka of southern Jiangxi province. Int J Clin Exp Pathol. 2015;8:15013-8.

He Y, Zhang Y, Chen X, Wang Q, Ling L, Xu Y. Glucose-6-phosphate dehydrogenase deficiency in the Han Chinese population: molecular characterization and genotype-phenotype association throughout an activity distribution. Sci Rep. 2020;10:17106.

Sirdah MM, Shubair ME, Al-Kahlout MS, Al-Tayeb JM, Prchal JT, Reading NS. Possible association of 3’ UTR +357 A>G, IVS11-nt 93 T>C, c.1311 C>T polymorphism with G6PD deficiency. Hematology. 2017;22:370-4.




How to Cite

Manco L, Bento C, Relvas L, Maia T, Ribeiro ML. Molecular Heterogeneity of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency in the Portuguese Population. Acta Med Port [Internet]. 2022 Sep. 23 [cited 2024 Feb. 21];36(2):81-7. Available from: