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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(5): 482-487, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34020738

RESUMO

OBJECTIVE: To analyze the screening results of glucose-6-phosphate dehydrogenase (G6PD) deficiency and gene mutation distribution of G6PD deficiency in preterm infants in Chengdu, China, in order to provide a basis for the improvement of G6PD screening process in preterm infants. METHODS: Fluorescent spot test for G6PD deficiency using dried blood spots was used for G6PD screening of 54 025 preterm infants born from January 1, 2015 to December 31, 2019 in Chengdu, and G6PD enzymology and gene detection were used for the diagnosis of 213 infants with positive screening results. RESULTS: Among the 54 025 preterm infants, 192 were diagnosed with G6PD deficiency, with an incidence rate of 3.55‰. The incidence rate of G6PD deficiency in preterm infants was higher than that in full-term infants in the same period of time and tended to increase year by year. Birth in summer, gestational age <32 weeks, and birth weight <2 500 g were influencing factors for the increase in false positive rate of screening (P < 0.05). The diagnostic accordance rate of genetic tests was significantly higher than that of enzyme activity assay in female infants (P < 0.05). Nine gene mutations were detected in Chengdu, without compound heterozygous mutation. Homozygous mutation was not detected in female infants. In the 80 infants with gene mutations, the top three gene mutations were c.1388G>A in 26 infants (32%), c.1376G>T in 21 infants (26%), and c.1024C>T in 13 infants (16%), accounting for 75%. There was a significant difference in pathogenicity grading among the three gene mutations (P < 0.001). The pairwise comparison showed that c.1024C>T had a significantly lower pathogenicity grade than c.1376G>T and c.1388G>A (P < 0.0167), suggesting that c.1376G>T and c.1388G>A had greater influence on enzyme activity than c.1024C>T. CONCLUSIONS: Screening for G6PD deficiency in preterm infants should be taken seriously. It is recommended to apply cold-chain transportation of samples in summer to reduce the false positive rate of primary screening for G6PD deficiency. Genetic tests should be promoted in girls with positive screening results to improve the detection rate of G6PD deficiency in preterm female infants. There are various types of gene mutations in preterm infants with G6PD deficiency in Chengdu, and infants with c.1024C>T mutation tend to have mild conditions.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , China/epidemiologia , Feminino , Testes Genéticos , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Mutação
2.
Artigo em Inglês | MEDLINE | ID: mdl-33719907

RESUMO

COVID-19 has become a major public health problem since December, 2019 and no highly effective drug has been found until now. Numbers of infected people and deaths by COVID-19 are increasing every day worldwide, therefore self-isolation and protection are highly recommended to prevent the spread of the virus and especially to protect major risk groups such as the elderly population and people with comorbidities including diabetes, hypertension, cancer, cardiovascular diseases and metabolic syndrome. On the other hand, young people without any secondary disease have died by COVID-19 as well. In this study we compared two male patients infected by COVID-19 at the same age and one of them was diagnosed with G6PD deficiency. Both COVID-19 and G6PD deficiency enhance the risk of hemolysis and thrombosis. Serum biochemistry, hemogram and immunological parameters showed that risk of hemolysis and thrombosis may increase in the G6PD deficient patient infected by COVID-19.


Assuntos
COVID-19/genética , Deficiência de Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/genética , Trombose/genética , Adulto , COVID-19/sangue , COVID-19/complicações , COVID-19/virologia , Deficiência de Glucosefosfato Desidrogenase/sangue , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/patologia , Hemólise/fisiologia , Humanos , Masculino , Fatores de Risco , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Trombose/sangue , Trombose/etiologia , Trombose/virologia
4.
Orphanet J Rare Dis ; 16(1): 103, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637102

RESUMO

BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency (G6PDd) newborn screening is still a matter of debate due to its highly heterogeneous birth prevalence and clinical expression, as well as, the lack of enough knowledge on its natural history. Herein, we describe the early natural clinical course and the underlying GDPD genotypes in infants with G6PDd detected by newborn screening and later studied in a single follow-up center. G6PDd newborns were categorized into three groups: group 1: hospitalized with or without neonatal jaundice (NNJ); group 2: non-hospitalized with NNJ; and group 3: asymptomatic. Frequencies of homozygous UGT1A1*28 (rs34983651) genotypes among G6PDd patients with or without NNJ were also explored. RESULTS: A total of 81 newborns (80 males, one female) were included. Most individuals (46.9%) had NNJ without other symptoms, followed by asymptomatic (42.0%) and hospitalized (11.1%) patients, although the hospitalization of only 3 of these patients was related to G6PDd, including NNJ or acute hemolytic anemia (AHA). Nine different G6PDd genotypes were found; the G6PD A-202A/376G genotype was the most frequent (60.5%), followed by the G6PD A-376G/968C (22.2%) and the Union-Maewo (rs398123546, 7.4%) genotypes. These genotypes produce a wide range of clinical and biochemical phenotypes with significant overlapping residual enzymatic activity values among class I, II or III variants. Some G6PD A-202A/376G individuals had enzymatic values that were close to the cutoff value (5.3 U/g Hb, 4.6 and 4.8 U/g Hb in the groups with and without NNJ, respectively), while others showed extremely low enzymatic values (1.1 U/g Hb and 1.4 U/g Hb in the groups with and without NNJ, respectively). Homozygosity for UGT1A1*28 among G6PDd patients with (11.9%, N = 5/42) or without (10.3%, N = 4/39) NNJ did not shown significant statistical difference (p = 0.611). CONCLUSION: Wide variability in residual enzymatic activity was noted in G6PDd individuals with the same G6PD genotype. This feature, along with a documented heterogeneous mutational spectrum, makes it difficult to categorize G6PD variants according to current WHO classification and precludes the prediction of complications such as AHA, which can occur even with > 10% of residual enzymatic activity and/or be associated with the common and mild G6PD A-376G/968C and G6PD A-202A/376G haplotypes.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Icterícia Neonatal , Feminino , Genótipo , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , Haplótipos , Humanos , Recém-Nascido , Masculino , Triagem Neonatal
5.
Acta Trop ; 217: 105864, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33607062

RESUMO

Accurate measurement of glucose-6-phosphate dehydrogenase (G6PD) activity is critical for malaria treatment as misclassification of G6PD deficiency could cause serious harm to patients. G6PD activity should be assessed in blood samples on the day of collection. Otherwise, specimens should be stored under suitable conditions to prevent loss of G6PD activity. Here, we assessed stability and integrity of G6PD testing in samples from normal controls, heterozygous females, and G6PD deficient individuals using water-soluble tetrazolium salts (WST-8) assay. Specimens were stored as ethylenediaminetetraacetic acid (EDTA) whole blood and dried blood spots (DBS) at various temperatures (37 °C, room temperature, 4 °C and -20 °C) and under different humidity conditions (with and without desiccant). G6PD normal samples were stable for up to 1 year when stored at -20 °C under controlled conditions, with 85% and 91% G6PD activity in EDTA whole blood and DBS in the presence of desiccant, respectively. Specimens from heterozygous females showed greater G6PD activity when stored as DBS, with 85% enzyme activity after 1 year of storage at -20 °C under controlled conditions in the presence of desiccant. G6PD deficient samples rapidly lost enzyme activity in all storage conditions tested. However, the reduction in G6PD enzyme activity in G6PD deficient samples did not interfere with G6PD classification. Samples stored under suitable conditions for G6PD testing will allow accurate measurement of enzyme activity, prevent misclassification of G6PD deficiency and enable safe and effective use of antimalarial drugs such as primaquine and tafenoquine.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Deficiência de Glucosefosfato Desidrogenase/sangue , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Programas de Rastreamento/métodos , Sais de Tetrazólio , Feminino , Deficiência de Glucosefosfato Desidrogenase/genética , Heterozigoto , Humanos , Masculino , Temperatura
6.
Acta Paediatr ; 110(6): 1935-1941, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33560519

RESUMO

AIM: This national retrospective Danish study described the characteristics of children diagnosed with glucose-6-phosphate dehydrogenase (G6PD) deficiency, an inherited X-linked recessive disorder that often affects children of Middle Eastern descent. METHODS: We studied children born between 1 January 2000 and 31 December 2017 and diagnosed with G6PD deficiency. They were identified from the Danish National Hospital Discharge Register and the Danish Database of Extreme Neonatal Hyperbilirubinaemia. RESULTS: There were 113 children diagnosed with G6PD deficiency, 67% were of Middle Eastern descent and they were frequently diagnosed before the onset of symptoms, based on known heredity. Of the 67 infants born in Denmark, 10% had extreme neonatal hyperbilirubinaemia and one developed kernicterus spectrum disorder, as did one child born in the Middle East. Most (61%) of the 33 children with jaundice received phototherapy, 12% had exchange transfusions and 18% received whole blood transfusions. After the neonatal period, 23% of the cohort had blood transfusions and 4% needed intensive care for acute haemolytic anaemia. The incidence of G6PD deficiency appeared to be severely underestimated. CONCLUSION: Many families from countries where G6PD deficiency is endemic move to Denmark and other Western countries. Greater awareness is essential to avoid chronic and potentially lethal, consequences.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Hiperbilirrubinemia Neonatal , Icterícia Neonatal , Criança , Dinamarca/epidemiologia , Transfusão Total , Glucosefosfato Desidrogenase , Deficiência de Glucosefosfato Desidrogenase/etnologia , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Lactente , Recém-Nascido , Oriente Médio/etnologia , Estudos Retrospectivos
7.
Trop Med Int Health ; 26(4): 462-468, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33415798

RESUMO

OBJECTIVE: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive disorder, is the commonest erythrocytic enzymopathy worldwide. Reliable diagnosis and severity prediction in G6PD-deficient/heterozygous females remain challenging. A recently developed flow cytometric test for G6PD deficiency has shown promise in precisely identifying deficient females. This paper presents our experiences with this test in a subtropical setting and presents a modification in flow cytometric data acquisition strategy. METHODS: The methaemoglobin reduction + ferryl Hb generation-based flow cytometric G6PD test was compared with the screening methaemoglobin reduction test (MRT) and confirmatory G6PD enzyme activity assay (EAA) in 20 G6PD-deficient males, 22 G6PD-heterozygous/deficient females and 20 controls. Stained cells were also assessed for bright/dim G6PD activity under a fluorescent microscope. RESULTS: Flow cytometry separated and quantified %bright cells in heterozygous/deficient females, objectively classifying them into 6 normal (>85% bright cells), 14 intermediate (10-85%) and two G6PD-deficient (<10% bright cells). Concordance with MRT was 89% (55/62 cases) and with EAA was 77% (48/62 cases). Fluorometrically predicted violet laser excitation (405-nm) with signal acquisition in the 425-475 nm region was a technical advancement noted for the first time in this paper. CONCLUSION: Flow cytometry/fluorescence microscopy represent technically straightforward methods for the detection and quantification of G6PD-deficient erythrocytes. Based on our results, we recommend their application as a first-line investigation to screen females who are prescribed an oxidant drug like primaquine or dapsone.


Assuntos
Ensaios Enzimáticos Clínicos/métodos , Testes Diagnósticos de Rotina/métodos , Eritrócitos/enzimologia , Citometria de Fluxo/métodos , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Glucosefosfato Desidrogenase/sangue , Heterozigoto , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Testes de Química Clínica/métodos , Contraindicações de Medicamentos , Feminino , Deficiência de Glucosefosfato Desidrogenase/enzimologia , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Lactente , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
8.
Free Radic Biol Med ; 164: 149-153, 2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33418115

RESUMO

NAD(P)H donates electrons for reductive biosynthesis and antioxidant defense across all forms of life. Glucose-6-phosphate dehydrogenase (G6PD) is a critical enzyme to provide NADPH. G6PD deficiency is present in more than 400 million people worldwide. This enzymopathy provides protection against malaria but sensitizes cells to oxidative stressors. Oxidative stress has been involved in the pathogenesis of the diabetic complications and several studies have provided evidences of a link between G6PD deficiency and type 2 diabetes (T2D). We hypothesized that a moderate overexpression of G6PD (G6PD-Tg) could protect ß-cells from age-associated oxidative stress thus reducing the risk of developing T2D. Here we report, that G6PD-Tg mice show an improved glucose tolerance and insulin sensitivity when compared to old age-matched Wild Type (WT) ones. This is accompanied by a decrease in oxidative damage and stress markers in the pancreas of the old Tg animals (20-24month-old). Pancreatic ß-cells progress physiologically towards a state of reduced responsiveness to glucose. In pancreatic islets isolated from G6PD-Tg and WT animals at different ages, and using electrophysiological techniques, we demonstrate a wider range of response to glucose in the G6PD-Tg cells that may explain the improvements in glucose tolerance and insulin sensitivity. Together, our results show that overexpression of G6PD maintains pancreatic ß-cells from old mice in a "juvenile-like" state and points to the G6PD dependent generation of NADPH as an important factor to improve the natural history of diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Deficiência de Glucosefosfato Desidrogenase , Células Secretoras de Insulina , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Deficiência de Glucosefosfato Desidrogenase/genética , Células Secretoras de Insulina/metabolismo , Camundongos , Estresse Oxidativo
9.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33468660

RESUMO

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common blood disorder, presenting multiple symptoms, including hemolytic anemia. It affects 400 million people worldwide, with more than 160 single mutations reported in G6PD. The most severe mutations (about 70) are classified as class I, leading to more than 90% loss of activity of the wild-type G6PD. The crystal structure of G6PD reveals these mutations are located away from the active site, concentrating around the noncatalytic NADP+-binding site and the dimer interface. However, the molecular mechanisms of class I mutant dysfunction have remained elusive, hindering the development of efficient therapies. To resolve this, we performed integral structural characterization of five G6PD mutants, including four class I mutants, associated with the noncatalytic NADP+ and dimerization, using crystallography, small-angle X-ray scattering (SAXS), cryogenic electron microscopy (cryo-EM), and biophysical analyses. Comparisons with the structure and properties of the wild-type enzyme, together with molecular dynamics simulations, bring forward a universal mechanism for this severe G6PD deficiency due to the class I mutations. We highlight the role of the noncatalytic NADP+-binding site that is crucial for stabilization and ordering two ß-strands in the dimer interface, which together communicate these distant structural aberrations to the active site through a network of additional interactions. This understanding elucidates potential paths for drug development targeting G6PD deficiency.


Assuntos
Coenzimas/química , Glucosefosfato Desidrogenase/química , Leucina/química , Mutação , NADP/química , Prolina/química , Sítios de Ligação , Clonagem Molecular , Coenzimas/metabolismo , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Deficiência de Glucosefosfato Desidrogenase/enzimologia , Deficiência de Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/patologia , Humanos , Cinética , Leucina/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , NADP/metabolismo , Prolina/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
10.
J Sci Food Agric ; 101(4): 1562-1571, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32869306

RESUMO

BACKGROUND: Favism is an acute hemolytic syndrome caused by fava bean (FB) ingestion. The purpose of this study was to investigate the possible influences of FB on the metabonomic profile of erythrocytes in glucose-6-phosphate dehydrogenase (G6PD)-deficient (G6PDx) and wild-type (WT) mice. RESULTS: Ninety-two metabolites were identified in the comparison of the G6PDx and WT groups. Eighty-seven metabolites were identified in the erythrocytes of WT and G6PDx mice after FB ingestion. Thirty-eight metabolites were identified in the comparison of the FB-treated G6PDx and the FB-treated WT mouse groups. Among them, the number of glycerophospholipids (GPLs) and polyunsaturated fatty acids (PUFAs) changed significantly, which suggests that GPLs and PUFAs may be responsible for FB stress. CONCLUSION: This study demonstrates that G6PD deficiency might affect the metabonomic profile of erythrocytes in response to FB. © 2020 Society of Chemical Industry.


Assuntos
Eritrócitos/metabolismo , Favismo/metabolismo , Deficiência de Glucosefosfato Desidrogenase/metabolismo , Vicia faba/metabolismo , Animais , Eritrócitos/enzimologia , Ácidos Graxos Insaturados/metabolismo , Favismo/enzimologia , Favismo/genética , Deficiência de Glucosefosfato Desidrogenase/enzimologia , Deficiência de Glucosefosfato Desidrogenase/genética , Glicerofosfolipídeos/metabolismo , Humanos , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout
11.
Blood Adv ; 4(23): 5942-5950, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33275767

RESUMO

Few previous studies have reported the effects of glucose-6-phosphate dehydrogenase (G6PD)-deficiency on child health in Africa. We conducted a case-control study in which cases (n = 6829) were children admitted, for any reason, to Kilifi County Hospital, Kenya, while controls (n = 10 179) were recruited from the surrounding community. Cases were subclassified based on their clinical and laboratory findings at admission. We calculated the prevalence of specific diseases by G6PD c.202 genotype, the only significant cause of G6PD-deficiency in this area, then estimated the association between genotype and admission with specific conditions using logistic regression.  Among neonates, the prevalence of jaundice was higher in both G6PD c.202T heterozygotes (40/88; 45.5%; P = .004) and homo/hemizygotes (81/134; 60.5%; P < .0001) than in wild-type homozygotes (157/526; 29.9%). Median bilirubin levels also increased across the groups, being highest (239 mmol/L; interquartile range 96-390 mmol/L) in G6PD c.202T homo/hemizygotes. No differences were seen in admission hemoglobin concentrations or the prevalence of anemia or severe anemia by G6PD c.202 genotype. On case control analysis, G6PD heterozygosity was negatively associated with all-cause hospital admission (odds ratio 0.81; 95% confidence interval 0.73-0.90; P < .0001) and, specifically, admission with either pneumonia or Plasmodium falciparum parasitemia; while, conversely, it was positively associated with Gram-positive bacteremia. G6PD c.202T homo/heterozygosity was positively associated with neonatal jaundice, severe pneumonia, the receipt of a transfusion, and in-patient death. Our study supports the conclusion that G6PD c.202T is a balanced polymorphism in which a selective advantage afforded to heterozygous females against malaria is counterbalanced by increased risks of neonatal jaundice, invasive bacterial infections, and anemia.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Estudos de Casos e Controles , Criança , Feminino , Genótipo , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Recém-Nascido , Quênia/epidemiologia
12.
Front Immunol ; 11: 545414, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33162974

RESUMO

Neonatal hemophagocytic lymphohistiocytosis (HLH) is a medical emergency that can be associated with significant morbidity and mortality. Often these patients present with familial HLH (f-HLH), which is caused by gene mutations interfering with the cytolytic pathway of cytotoxic T-lymphocytes (CTLs) and natural killer cells. Here we describe a male newborn who met the HLH diagnostic criteria, presented with profound cholestasis, and carried a maternally inherited heterozygous mutation in syntaxin-binding protein-2 [STXBP2, c.568C>T (p.Arg190Cys)] in addition to a severe pathogenic variant in glucose 6-phosphate dehydrogenase [G6PD, hemizygous c.1153T>C (Cys385Arg)]. Although mutations in STXBP2 gene are associated with f-HLH type 5, the clinical and biological relevance of the p.Arg190Cys mutation identified in this patient was uncertain. To assess its role in disease pathogenesis, we performed functional assays and biochemical and microscopic studies. We found that p.Arg190Cys mutation did not alter the expression or subcellular localization of STXBP2 or STX11, neither impaired the STXBP2/STX11 interaction. In contrast, forced expression of the mutated protein into normal CTLs strongly inhibited degranulation and reduced the cytolytic activity outcompeting the effect of endogenous wild-type STXBP2. Interestingly, arginine 190 is located in a structurally conserved region of STXBP2 where other f-HLH-5 mutations have been identified. Collectively, data strongly suggest that STXBP2-R190C is a deleterious variant that may act in a dominant-negative manner by probably stabilizing non-productive interactions between STXBP2/STX11 complex and other still unknown factors such as the membrane surface or Munc13-4 protein and thus impairing the release of cytolytic granules. In addition to the contribution of STXBP2-R190C to f-HLH, the accompanied G6PD mutation may have compounded the clinical symptoms; however, the extent by which G6PD deficiency has contributed to HLH in our patient remains unclear.


Assuntos
Exocitose/genética , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Deficiência de Glucosefosfato Desidrogenase/genética , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Proteínas Munc18/genética , Mutação , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Apoptose/genética , Apoptose/imunologia , Biomarcadores , Citotoxicidade Imunológica , Suscetibilidade a Doenças , Expressão Gênica , Estudos de Associação Genética , Deficiência de Glucosefosfato Desidrogenase/complicações , Humanos , Recém-Nascido , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfo-Histiocitose Hemofagocítica/complicações , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Modelos Moleculares , Proteínas Munc18/química , Proteínas Munc18/metabolismo , Conformação Proteica , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , Relação Estrutura-Atividade , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo
13.
Zhonghua Yu Fang Yi Xue Za Zhi ; 54(11): 1275-1282, 2020 Nov 06.
Artigo em Chinês | MEDLINE | ID: mdl-33147929

RESUMO

Objective: To reveal the relationship between G6PD genotypes and the G6PD enzyme activities in dried blood spots of newborn screening. Methods: Simple random sampling procedure was used in this study. The fluorescence PCR melting curve analysis was performed to classify G6PD gene variants in 635 neonates coming from Guangzhou Newborn Screening Center during October 1 to 20, 2016, including 15 reported variants. Those samples consisted of 377 cases with screening positive results (261 from males and 116 from females) and 258 cases with screening negative results (32 from males and 226 from females). The cut-off value of G6PD was less than 2.6 U/g Hb in dry blood spots. Sanger sequencing for G6PD gene was used in 7 cases with screening negative results under simple random sampling. One-way ANOVA and least significant difference method (LSD) test were performed to compare the difference of G6PD activity among genotypes. Results: The top 6 frequency of G6PD gene variants were c.1388G>A(35.07%), c.1376G>T(32.13%), c.95A>G(12.72%), c.871G>A(8.32%), c.1024C>T(4.08%) and c.392G>T(2.28%), accounting for 94.62% of all variant alleles (580/613). A total of 253 males positive for enzyme activity were detected to have gene mutations. The positive rate of G6PD enzyme activity was 98.06%(253/258). The mean values of G6PD activities for c.1376G>T,c.95A>G and c.1388G>A were 0.85, 1.10 and 1.28 U/g Hb, respectively. There were significant differences among the three groups (F=28.7, P<0.01). A total of 105 females positive for enzyme activity were detected to have gene mutations. The positive rate of G6PD enzyme activity was 90.52%(105/116). The positive rate of G6PD enzyme activity was 26.95% among 256 females with one point mutation while it was 83.72% in females with multi-allele variants. The G6PD activity of heterozygous females was (2.9±0.8) U/g Hb, which was significant higher than that of females with multi-allele variants (1.5±1.0) U/g Hb (t=8.6,P<0.01). Conclusions: G6PD activities in dried blood spots were related to G6PD genotypes in males. They were also associated with the numbers of allele variants in females. Newborn screening for G6PD deficiency can be used to detect most of G6PD-deficient hemizygotes and female patients with multi-allele variants, which is helpful for preventing neonatal jaundice and medicine application.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Glucosefosfato Desidrogenase , Feminino , Genótipo , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/genética , Heterozigoto , Humanos , Recém-Nascido , Masculino , Mutação , Triagem Neonatal
14.
Sci Rep ; 10(1): 17106, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051526

RESUMO

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common hereditary disorder in China. The existing prevalence and molecular epidemiology of G6PD deficiency in China were geographically limited. In this study, the spectrum of G6PD gene mutations was well characterized in a large and diverse population all over the country; and the correlation of genotype and enzyme activity phenotype was explored for the first time. The results showed that the overall prevalence of G6PD deficiency in China was 2.10% at the national level. The top six common mutations were c.1388 G>A, c.1376 G>T, c.95 A>G, c.392 G>T, c.871 G>A and c.1024 C>T, accounting for more than 90% of G6PD deficient alleles. Compound mutation patterns were frequently observed in females with severe deficiency. The distribution of G6PD activities depended on the type of mutation patterns and genders. Hemizygote, homozygote, and compound heterozygote were predominantly associated with severe G6PD deficiency, whereas heterozygotes with single mutation mainly presented moderate enzyme deficiency. A significant gap between G6PD activities in hemizygous and normal males was observed, and yet, the overall distribution of that in females carrying missense mutations was a continuum from G6PD severely deficient to normal. This is the first report of discussing the association between G6PD genetic variants in the Chinese and enzyme activity phenotypes.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Deficiência de Glucosefosfato Desidrogenase/genética , Adulto , China/epidemiologia , Feminino , Estudos de Associação Genética , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Estudos Prospectivos , Adulto Jovem
15.
Free Radic Biol Med ; 161: 84-91, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33038530

RESUMO

There is a marked variation in mortality risk associated with COVID-19 infection in the general population. Low socioeconomic status and other social determinants have been discussed as possible causes for the higher burden in African American communities compared with white communities. Beyond the social determinants, the biochemical mechanism that predisposes individual subjects or communities to the development of excess and serious complications associated with COVID-19 infection is not clear. Virus infection triggers massive ROS production and oxidative damage. Glutathione (GSH) is essential and protects the body from the harmful effects of oxidative damage from excess reactive oxygen radicals. GSH is also required to maintain the VD-metabolism genes and circulating levels of 25-hydroxyvitamin D (25(OH)VD). Glucose-6-phosphate dehydrogenase (G6PD) is necessary to prevent the exhaustion and depletion of cellular GSH. X-linked genetic G6PD deficiency is common in the AA population and predominantly in males. Acquired deficiency of G6PD has been widely reported in subjects with conditions of obesity and diabetes. This suggests that individuals with G6PD deficiency are vulnerable to excess oxidative stress and at a higher risk for inadequacy or deficiency of 25(OH)VD, leaving the body unable to protect its 'oxidative immune-metabolic' physiological functions from the insults of COVID-19. An association between subclinical interstitial lung disease with 25(OH)VD deficiencies and GSH deficiencies has been previously reported. We hypothesize that the overproduction of ROS and excess oxidative damage is responsible for the impaired immunity, secretion of the cytokine storm, and onset of pulmonary dysfunction in response to the COVID-19 infection. The co-optimization of impaired glutathione redox status and excess 25(OH)VD deficiencies has the potential to reduce oxidative stress, boost immunity, and reduce the adverse clinical effects of COVID-19 infection in the AA population.


Assuntos
COVID-19/patologia , Deficiência de Glucosefosfato Desidrogenase/genética , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Deficiência de Vitamina D/genética , Afro-Americanos/estatística & dados numéricos , COVID-19/mortalidade , Síndrome da Liberação de Citocina/patologia , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/metabolismo , Glutationa/metabolismo , Humanos , SARS-CoV-2 , Vitamina D/análogos & derivados , Vitamina D/metabolismo
16.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1757-1761, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067986

RESUMO

OBJECTIVE: To explore the clinical significance of G6PD gene mutation detection in female heterozygote with G6PD deficiency. METHODS: G6PD activity and fourteen common G6PD gene mutations in female blood samples were detected by biochemical phenotype detection and PCR-reverse dot blotting, respectively. Unidentified genotype of G6PD positive samples was further ascertained by direct DNA sequencing. The results from two methods were compared and analyzed. RESULTS: A total of 493 unrelated females were enrolled, and the G6PD activity and G6PD mutations was detected. Among them, 473 females were found to be normal in G6PD activity and 20 females with G6PD deficiency, and the detection rate by G6PD activity method was 4.06%. In all enrolled females, G6PD gene mutations, including the mutation of c.1311 C>T, were identified in 130 females, and the detection rate was 26.3%. Detection rate of the mutations that can lead to G6PD deficiency was 8.11%. The detection rates between the two methods were significantly different (P<0.01). The misdiagnosis rate of the G6PD activity detection reached 49. 94% for the female heterozygotes. Eight G6PD mutations and 13 mutation patterns were identified in the research, and most of mutation patterns were single nucleotide missense mutation. In addition to c.1311C>T mutation, the most common mutations were c.1376G>T, c.1388G>A and c.95 A>G. G6PD mutations were identified in 19 of 20 females with G6PD deficiency, and were also detected in 21 of 473 females with normal G6PD activity, of which the rate of heterozygous mutation was 90.88%. CONCLUSION: The phenotype detection based on G6PD enzyme activity alone is not sufficient for the diagnosis of female heterozygotes. The detection of G6PD mutations that covers the common mutations in specified region can effectively identify the female heterozygotes with normal G6PD activity.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Feminino , Genótipo , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/genética , Heterozigoto , Humanos , Mutação
17.
Mol Genet Genomic Med ; 8(12): e1540, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33128437

RESUMO

BACKGROUND: Although glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited disorder in the Chinese population, there is scarce evidence regarding the epidemiology, evolutionary origin, and malaria-induced positive selection effects of G6PD-deficient alleles in various Chinese ethnic populations. METHODS: We performed a large population-based screening (n = 15,690) to examine the impact of selection on human nucleotide diversity and to infer the evolutionary history of the most common deficiency alleles in Chinese populations. RESULTS: The frequencies of G6PD deficiency ranged from 0% to 11.6% in 12 Chinese ethnic populations. A frequency map based on geographic information showed that G6PD deficiency was highly correlated with historical malaria prevalence in China and was affected by altitude and latitude. The five most frequently occurring G6PD gene variants were NM_001042351.3:c.1376G>T, NM_001042351.3:c.1388G>A, NM_001042351.3:c.95A>G, NM_001042351.3:c.1311T>C, and NM_001042351.3:c.1024C>T, which were distributed with ethnic features. A pathogenic but rarely reported variant site (NM_001042351.3:c.448G>A) was identified in this study. Bioinformatic analysis revealed a strong and recent positive selection targeting the NM_001042351.3:c.1376G>T allele that originated in the past 3125 to 3750 years and another selection targeting the NM_001042351.3:c.1388G>A allele that originated in the past 5000 to 6000 years. Additionally, both alleles originated from a single ancestor. CONCLUSION: These results indicate that malaria has had a major impact on the Chinese genome since the introduction of rice agriculture.


Assuntos
Alelos , Evolução Molecular , Deficiência de Glucosefosfato Desidrogenase , Glucosefosfato Desidrogenase/genética , Malária , Mutação , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/enzimologia , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/parasitologia , Humanos , Malária/enzimologia , Malária/epidemiologia , Malária/genética , Masculino , Prevalência
18.
PLoS Negl Trop Dis ; 14(9): e0008697, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925910

RESUMO

The proportion of Plasmodium vivax malaria among all malarias is increasing worldwide. Treatment with 8-aminoquinolines remain the only radical cure. However, 8-aminoquinolines can cause severe hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. The population of the multi-ethnic Chittagong Hill Tracts (CHT) carry the highest malaria burden within Bangladesh. As in many countries the national treatment guidelines recommend 8-aminoquinoline based radical cure without routine G6PD deficiency (G6PDd) testing to guide treatment. Aim of this study was to determine the need for routine testing within a multi-ethnic population by assessing the prevalence of G6PDd among the local population. Participants from 11 ethnicities were randomly selected and malaria status was assessed by microscopy, rapid diagnostic test (RDT) and polymerase chain reaction (PCR). G6PD status was determined by spectrophotometry and G6PD genotyping. The adjusted male median (AMM) was defined as 100% G6PD activity, participants were categorized as G6PD deficient (<30% activity), G6PD intermediate (30% to 70% activity) or G6PD normal (>70% activity). Median G6PD activities between ethnicities were compared and the association between G6PD activity and malaria status was assessed. 1002 participants were enrolled and tested for malaria. G6PD activity was measured by spectrophotometry in 999 participants and host G6PD genotyping undertaken in 323 participants. Seven participants (0.7%) had peripheral parasitaemia detected by microscopy or RDT and 42 by PCR (4.2%). Among 106 participants (32.8%) with confirmed genotype, 99 (93.4%) had the Mahidol variant. The AMM was 7.03U/gHb with 90 (9.0%) G6PD deficient participants and 133 (13.3%) with intermediate G6PD activity. Median G6PD activity differed significantly between ethnicities (p<0.001), proportions of G6PD deficient individuals ranged from 2% to 26% but did not differ between participants with and without malaria. The high G6PDd prevalence and significant variation between ethnicities suggest routine G6PDd testing to guide 8-aminoquinoline based radical in the CHT and comparable settings.


Assuntos
Grupos Étnicos/genética , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Adulto , Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Bangladesh/epidemiologia , Testes Diagnósticos de Rotina , Feminino , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Humanos , Malária Vivax/complicações , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prevalência , Adulto Jovem
19.
Redox Biol ; 36: 101639, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32863204

RESUMO

Fyn is a tyrosine kinase belonging to the Src family (Src-Family-Kinase, SFK), ubiquitously expressed. Previously, we report that Fyn is important in stress erythropoiesis. Here, we show that in red cells Fyn specifically stimulates G6PD activity, resulting in a 3-fold increase enzyme catalytic activity (kcat) by phosphorylating tyrosine (Tyr)-401. We found Tyr-401 on G6PD as functional target of Fyn in normal human red blood cells (RBC), being undetectable in G6PD deficient RBCs (G6PD-Mediterranean and G6PD-Genova). Indeed, Tyr-401 is located to a region of the G6PD molecule critical for the formation of the enzymatically active dimer. Amino acid replacements in this region are mostly associated with a chronic hemolysis phenotype. Using mutagenesis approach, we demonstrated that the phosphorylation status of Tyr401 modulates the interaction of G6PD with G6P and stabilizes G6PD in a catalytically more efficient conformation. RBCs from Fyn-/-mice are defective in G6PD activity, resulting in increased susceptibility to primaquine-induced intravascular hemolysis. This negatively affected the recycling of reduced Prx2 in response to oxidative stress, indicating that defective G6PD phosphorylation impairs defense against oxidation. In human RBCs, we confirm the involvement of the thioredoxin/Prx2 system in the increase vulnerability of G6PD deficient RBCs to oxidation. In conclusion, our data suggest that Fyn is an oxidative radical sensor, and that Fyn-mediated Tyr-401 phosphorylation, by increasing G6PD activity, plays an important role in the physiology of RBCs. Failure of G6PD activation by this mechanism may be a major limiting factor in the ability of G6PD deficient RBCs to withstand oxidative stress.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Glucosefosfato Desidrogenase , Animais , Eritrócitos , Glucose-6-Fosfato , Deficiência de Glucosefosfato Desidrogenase/genética , Hemólise , Camundongos
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