The Normal Human Female as a Mosaic of X-Chromosome Activity: Studies Using the Gene for G-6-Pd-Deficiency as a Marker

Beutler, Ernest; Yeh, Mary; Fairbanks, Virgil F.

doi:10.1073/pnas.48.1.9

Cited by 455 publications

(173 citation statements)

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“…Firstly, the small sample size of females did not allow a determination of the presence of possible linkage between the G6PD locus and other genetic factors which may be involved. 30 Secondly, the location of the G6PD gene on the X chromosome and the subsequent variable X-chromosome inactivation, implies that the expression of G6PD deficiency differs markedly among heterozygote females, 31 and therefore that these females do not constitute a homogeneous group.…”

Section: Discussionmentioning

confidence: 99%

Human genetic factors related to susceptibility to mild malaria in Gabon

Migot-Nabias¹,

Mombo²,

Luty³

et al. 2000

Genes Immun

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Several human genetic factors, including red blood cell polymorphisms (ABO blood group, sickle-cell trait, G6PD deficiency) as well as point mutations in the mannose binding protein (MBP) and in the promoter regions of both the TNF-␣ and NOS2 genes, influence the severity of disease due to infection with Plasmodium falciparum. We assessed their impact on mild P. falciparum malaria, as part of a longitudinal investigation of clinical, parasitological and immunological parameters in a cohort of 300 Gabonese schoolchildren. We found the following frequencies: blood group O (0.54), sicklecell trait (0.23), G6PD deficiency (0.09), MBP gene mutations (0.34), TNF-␣ promoter mutations (at positions −238: 0.17 and −308: 0.22) and NOS2 promoter mutation (0.18). Blood group O or hemoglobin AA were associated with protection against higher parasitemia. Girls with normal G6PD enzyme activity were protected against clinical malaria attacks. In addition, we demonstrated for the first time that the mutation at position −238 of the gene coding for the promoter region of TNF-␣ was positively correlated with the level of the antibody response specific for epitopes of the antigens MSA-2 and RAP-1 of P. falciparum. Genes and Immunity (2000) 1, 435-441.

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Section: Discussionmentioning

confidence: 99%

Human genetic factors related to susceptibility to mild malaria in Gabon

Migot-Nabias¹,

Mombo²,

Luty³

et al. 2000

Genes Immun

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“…The patient' chronic hemolytic anemia is caused by an almost exclusively expression of the mutant G6PD allele, as shown in reticulocytes and leukocytes G6PD mRNA studies. HUMARA assays (2). The arrow indicates the predominantly active chromosome: as in the inactive X chromosome the HhaI site is methylated, no digestion occurs and PCR amplification takes place; in the active X chromosome, the regular HhaI digestion leads to disruption of the HUMARA gene, preventing PCR amplification.…”

Section: Humara Assaysmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Manco¹,

Pereira²,

Relvas³

et al. 2011

Blood Cells, Molecules, and Diseases

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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...

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“…The degree of enzyme deficiency and severity of clinical complications depend on the exact G6PD mutation involved. The Mediterranean and certain Southeast Asian variants are associated with less than 10% residual enzyme activity (Class II deficiency) [4] and generally more severe clinical manifestations than the African A-form, which provides 10-60% of residual activity (Class III). Since the G6PD gene is found on the X-chromosome, there is a higher risk of haemolytic crisis in males (homozygous) and homozygous females with mutations than in heterozygous females, although heterozygotes are also at some risk due to X-chromosome inactivation [5].…”

Section: Introduction:-mentioning

confidence: 99%

Description of Haematological Trend of Vivax Malaria Treated With Chloroquine and Primaquine in Eastern Afghanistan Laghman Province.

Ziar¹,

ijar²

2018

IJAR

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Background: Malaria is a major cause of morbidity and recognized as a heavy burden on health system in Afghanistan.,95% of confirmed cases are due to P. vivax which is challenging because of the nonspecific nature of the signs and symptoms, relapses of the infection weeks to months after the initial attack for up to about 2 years and requires radical treatment but still not well-administered due to fear of hemolysis as according the literature the Mediterranean variant of G6PD is common in many ethnic groups in Afghanistan, Primary objective: To determine the normal hematological response, following P. vivax infection and treatment in malaria endemic population in Afghanistan. Secondary objectives: 1) To measure the hemoglobin difference before and after treatment. 2)To assess independent risk factors associated with anaemia. 3)To assess the time to recovery from anaemia after administration of chloroquine+primaquine and compare this with chloroquine alone 4) To assess the effect of primaquine mg/kg dose on hemoglobin reduction and time to anaemia recovery. 5) To describe evidence of hemolysis in patients receiving primaquine. 6) To estimate the prevalence of G6PD deficiency. Method: This was a single-arm observational cohort study for descriptive prospective analysis of clinical, Laboratory, and demographic data from outpatients with P. vivax malaria. Those who had parasitological confirmed Plasmodium vivax with thick blood smear examination who were meeting study inclusion criteria, gave consent and enrolled in the study, had their G6PD status, CBC including the WBC count, hemoglobin values, and platelets counts performed and after a careful clinical assessment the treatment prescribed according to the malaria treatment protocol (14). Results: Overall 221 patients have been recorded, however, the target were 250 patients but, 29 of them were recorded as defaulters. Adherence to 14 days PQ therapy in G6PD normal patients were excellent (100%), all patient in intervention group fully completed 14 days PQ therapy. Conclusion: Anti-relapse therapy is recommended for all confirmed PV cases. In the current situation, G6PD RDT can be used at lower health facilities.

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The Normal Human Female as a Mosaic of X-Chromosome Activity: Studies Using the Gene for G-6-Pd-Deficiency as a Marker

Cited by 455 publications

References 6 publications

Human genetic factors related to susceptibility to mild malaria in Gabon

Human genetic factors related to susceptibility to mild malaria in Gabon

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

Description of Haematological Trend of Vivax Malaria Treated With Chloroquine and Primaquine in Eastern Afghanistan Laghman Province.

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