Chronic hemolytic anemia is associated with a new glucose-6-phosphate dehydrogenase in-frame deletion in an older woman

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is usually observed in hemizygote males and very rarely in females. The G6PD class 1 variants, very uncommon, are associated with chronic hemolytic anemia. Here we report a Portuguese woman who suffered in her sixties from a chronic hemolytic anemia due to G6PD deficiency. Molecular studies revealed heterozygosity for an in-frame 18-bp deletion, mapping to exon 10 leading to a deletion of 6 residues, 362-367 (LNERKA), which is a novel G6PD class 1 variant, G6PD Tondela. Two of her three daughters, asymptomatic, with G6PD activity within the normal range, are heterozygous for the same deletion. The patient's leukocyte and reticulocyte mRNA studies revealed an almost exclusive expression of the mutant allele, explaining the chronic hemolytic anemia. Patient whole blood genomic DNA HUMARA assay showed a balanced pattern of X chromosome inactivation (XCI), but granulocyte DNA showed extensive skewing, harboring the mutated allele, implying that in whole blood, lymphocyte DNA, with a very long lifetime, may cover up the current high XCI skewing. This observation indicates that HUMARA assay in women should be assessed in granulocytes and not in total leukocytes. © 2011 Elsevier Inc. All rights reserved. IntroductionX chromosome inactivation (XCI) is an epigenetic process, unique in mammals, by which one of the two X chromosomes in each cell is inactivated in females early in embryogenesis [1]. Therefore, women are a mosaic of paternal and maternal active X chromosome and a theoretical 1:1 ratio of two cell lines with inactive maternal to paternal X chromosome could be expected. The XCI ratio is usually assessed analyzing protein variants directly in heterozygous females' cells [2], transcribed mRNA expression [3] or DNA methylation status of polymorphic X-linked genes, such as the human androgen receptor (HUMARA) gene [4]. Deviation from the theoretical 1:1 ratio between the 2 parental alleles is called skewing. Several reports using the HUMARA assay show that the incidence of skewing is relatively low at birth and in adult non-hematopoietic tissues, but higher and agedependent in hematopoietic cells, with 30-40% of healthy elderly women reported to have skewing (greater than 75% expression of one parental X chromosome) [5][6][7][8][9][10][11][12]. T lymphocytes show less evidence of skewing with age than neutrophils, presumably reflecting the neutrophils' short half-life, whereas T lymphocytes are long-living cells, and in consequence, some T cells are produced near the time of study but others are derived from earlier stem cells [11][12][13]. This agerelated skewing in blood cells has been attributed to clonality as a consequence of hematopoietic stem cell senescence [5,7,9]. Swierczek et al. report a discrepancy between the skewed XCI observed in blood cells of 45 elderly women (ages 65-92 years; mean, 81.3 years) using the methylation-based HUMARA assay and a transcriptional based assay: with HUMARA assay in granulocyte DNA they found an ag...

Identification and Characterization of the Glucose-6-Phosphate Dehydrogenase Gene Family in the Para Rubber Tree, Hevea brasiliensis

“…NADPH not only acts to maintain the output of reduced glutathione (GSH), but is also involved in activity of plasma membrane (PM) NADPH oxidase which would result in hydrogen peroxide (H 2 O 2 ) accumulation ( Leopold et al, 2003 ; Mendez et al, 2011 ). Any decrease in G6PDH activity upsets internal redox balance, leading to disorders of signaling pathways and cell cycles in plant ( Manco et al, 2011 ). G6DPH is a key enzyme in rice, responding to salt stress to maintain cell redox balance ( Zhang et al, 2013 ).…”

Glucose-6-Phosphate Dehydrogenase Deficiency Cases with Different Clinical Findings: Daughter with Hemolytic Anemia and Asymptomatic Father

“…Bu varyantın homozigot kadınlarında ve erkeklerinde enzim aktivitesi normalin %5'inin altındadır. Heterozigot kadınlarda enzim düzeyi normal bile saptansa lyonizasyon nedeniyle klinik bulgular görülebilmektedir (7). Sıklıkla bakla tüketimine bağlı olarak akut ve şiddetli hemolitik kriz ve buna bağlı ölümler ile karşılaşılabilmektedir (1).…”

“…sınıf-V Enzim aktivitesi yüksektir. (7,8). Hastamızda de novo mutasyona bağlı bir enzim eksikliği düşünülürken, babada da enzim düzeyi düşük olduğu için bu fikirden uzaklaşıldı.…”

Heterogeneidade Molecular da Deficiência em Glicose-6-Fosfato Desidrogenase (G6PD) na População Portuguesa

“…This retrospective study assessed the mutational profile of 138 Portuguese individuals with G6PD deficiency (101 males and 37 females; aged between 2 and 74 years), diagnosed between 1994 and 2020, based on recent data and results obtained in past periods, some of which have been published. 15,16 All individuals, unrelated and with no known sub-Saharan ancestry, were mostly from central Portugal (about 65%), but also from the southern (about 15%) and northern (about 8%) regions, and the Azores archipelago (about 2%). In about 10% of the cases, it was not possible to identify the place of birth.…”