A trade off between catalytic activity and protein stability determines the clinical manifestations of glucose-6-phosphate dehydrogenase (G6PD) deficiency

Background: G6PD deficiency is an inherited X-linked recessive condition leading to insufficient levels of glucose-6-phosphate dehydrogenase, thus causing hemolytic anaemia under certain circumstances. Materials and Methods: Our study is explorative for cases admitted to Jordan University Hospital. The studied parameters include demographics, clinical manifestations, biochemical markers including Hb level, WBC count, liver enzymes, and blood grouping. Results: Most of the patients were admitted to the emergency unit (53.13%). Individuals who were Rh-positive represented 57.81%, while patients of AB blood group accounted for 75%. The mean values were 4.81 years (age), 29.06 hours (time-to-hospital admission), 38.10 degree Celsius (temperature), 6.11 gm/dl (Hb), 13242.19 (WBC count), 343.20 U/L (S. ALP), and 50.98 IU/L (S. ALT). There was no significant difference between males and females or between favism-induced versus drug-induced hemolytic episodes. AB and Rh positive blood groups are of a protective effect in relation to liver enzymes. Patients who were admitted to the hospital within 24 hours from having clinical manifestations had a better prognosis. Conclusion: This study is the first inferential research on G6PD deficiency from the Middle East to explore cases from one of the largest healthcare centres in Jordan. The role of blood grouping should be investigated prospectively.

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Establishment of a stable zg6pdM118-144 transgenic zebrafish model of glucose-6-phosphate dehydrogenase deficiency

10.1101/2020.04.28.066779 ◽

2020 ◽

Author(s):

Hai-Xiong Xia ◽

Yan-Hua Zhou ◽

Yuan-Yuan Tuo ◽

Ping-Ping Ren ◽

Jin Song ◽

...

Keyword(s):

G6pd Deficiency ◽

Genetic Defect ◽

Clinical Manifestations ◽

Wide Distribution ◽

Health Concern ◽

Transgenic Zebrafish ◽

Zebrafish Model ◽

Malaria Therapy ◽

Glucose 6 Phosphate Dehydrogenase

AbstractGlucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common genetic defect and enzymopathy with a wide distribution and increased public health concern, predisposes subjects succumb to oxidative stress. G6PD deficiency has been associated with hemolysis. Clinically, G6PD deficiency is asymptomatic and the clinical manifestations occur with the exposure to certain agents. Due to the lack of suitable animal models that can predict the clinical hemolytic potential of drugs, it needs an appropriate research model to fully recapitulate the manifestations of G6PD deficiency in clinic, to optimize the malaria therapy and promote anti-malarias development. The present study has displayed a stable transgenic Tg(zgata1-g6pdM118-144-egfp) zebrafish model with G6PD deficiency which mimics the clinical features of G6PD deficiency phenotypically and functionally. The findings showed that there was an inadequate level of reduced GSH in the transgenic Tg(zgata1-g6pdM118-144-egfp) zebrafish line in the presence or absence of α-naphthol, compared to the wildtype zebrafish, indicating an attenuation of g6pd activity in the transgenic zebrafish line. In addition, the observations show that there is a less abundance of g6pd in the transgenic Tg(zgata1-g6pdM118-144-egfp) zebrafish line. On the other hand, there is no morphological abnormality in the transgenic Tg(zgata1-g6pdM118-144-egfp) zebrafish line. Taken together, our work has delivered a novel stable transgenic zebrafish model of G6PD deficiency that will facilitate the mechanistic and functional elucidation for the role of G6PD in erythrocytic pathophysiology. This model will promote the translational research for the drug development, in particular, for anti-malarias development.

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Clinical Manifestations and Therapeutic Findings of the Children with Glucose-6-Phosphate Dehydrogenase Deficiency Presenting Favism

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320999200818182905 ◽

2020 ◽

Vol 20 ◽

Author(s):

Fariba Tarhani ◽

Alireza Nezami ◽

Ghobad Heidari ◽

Babak Abdolkarimi

Keyword(s):

G6pd Deficiency ◽

Dehydrogenase Deficiency ◽

Clinical Manifestations ◽

Descriptive Study ◽

Cross Sectional ◽

Common Complaint ◽

The Mean ◽

Fava Beans ◽

Glucose 6 Phosphate Dehydrogenase ◽

Hydration Therapy

Aim: Favism is characterized as acute anemia, due to Glucose-6-phosphate dehydrogenase (G6PD) deficiency as a result of fava beans intake. It is associated with paleness, jaundice, and hemoglobinuria. In this study, signs, symptoms and therapeutic findings of the patients with hemolysis due to G6PD deficiency were investigated in Shahid Madani Hospital of Khorramabad, Lorestan. Methods: This is a single-center cross-sectional descriptive study that was conducted on all children with G6PD deficiencyinduced hemolysis. Results: 308 children (64.3% male and 35.7% female) were included in this study. The most common complaint was jaundice (82.5%) and the most common cause of hemolysis was the intake of fava bean (85.7%). 68% of the children were treated with hydration/fluid therapy. Blood transfusion was conducted in 36.36% of the cases and the mean of blood administered was 18.9 cc/kg. Conclusion: In this study, hydration therapy was performed in most of the children presenting favism. Also, the incorrect calculation of the amount of blood needed for transfusion has increased the frequency of blood transfusions and prolonged hospitalization time.

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Combined effects of double mutations on catalytic activity and structural stability contribute to clinical manifestations of glucose-6-phosphate dehydrogenase deficiency

Scientific Reports ◽

10.1038/s41598-021-03800-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Phonchanan Pakparnich ◽

Sirapapha Sudsumrit ◽

Mallika Imwong ◽

Teeraporn Suteewong ◽

Kamonwan Chamchoy ◽

...

Keyword(s):

Catalytic Activity ◽

Structural Stability ◽

Clinical Manifestations ◽

Enzyme Deficiency ◽

Combined Effects ◽

Wild Type ◽

Wild Type Enzyme ◽

Catalytically Active ◽

Glucose 6 Phosphate Dehydrogenase ◽

Structurally Stable

AbstractGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans, affecting ~ 500 million worldwide. A detailed study of the structural stability and catalytic activity of G6PD variants is required to understand how different mutations cause varying degrees of enzyme deficiency, reflecting the response of G6PD variants to oxidative stress. Furthermore, for G6PD double variants, investigating how two mutations jointly cause severe enzyme deficiency is important. Here, we characterized the functional and structural properties of nine G6PD variants: G6PD Gaohe, G6PD Mahidol, G6PD Shoklo, G6PD Canton, G6PD Kaiping, G6PD Gaohe + Kaiping, G6PD Mahidol + Canton, G6PD Mahidol + Kaiping and G6PD Canton + Kaiping. All variants were less catalytically active and structurally stable than the wild type enzyme, with G6PD double mutations having a greater impact than single mutations. G6PD Shoklo and G6PD Canton + Kaiping were the least catalytically active single and double variants, respectively. The combined effects of two mutations were observed, with the Canton mutation reducing structural stability and the Kaiping mutation increasing it in the double mutations. Severe enzyme deficiency in the double mutants was mainly determined by the trade-off between protein stability and catalytic activity. Additionally, it was demonstrated that AG1, a G6PD activator, only marginally increased G6PD enzymatic activity and stability.

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Establishment of a stable transgenic g6pdM1315-1443 zebrafish line with glucose-6-phosphate dehydrogenase deficiency

10.1101/2020.04.30.068981 ◽

2020 ◽

Author(s):

Lu-Jun Shang ◽

Jin Song ◽

Hai-Xiong Xia ◽

Yuan-Yuan Tuo ◽

Ping-Ping Ren ◽

...

Keyword(s):

G6pd Deficiency ◽

Human Subjects ◽

Clinical Manifestations ◽

Transgenic Zebrafish ◽

Hemoglobin Content ◽

Zebrafish Model ◽

Disease States ◽

Clinical Syndromes ◽

Pericardial Edema ◽

Glucose 6 Phosphate Dehydrogenase

ABSTRACTGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzymopathy in humans and is associated with a predisposition to hemolysis. However, there are few animal models to that adequately mimic associated human disease states that could be used to evaluate strategies to address clinical syndromes attributable to G6PD deficiency. In the present study, we aimed to establish a stable transgenic zebrafish model of G6PD deficiency that recapitulates the clinical manifestations of G6PD deficiency. We incorporated a stable transgene of G6PD lacking nucleotides from 1315 to 1443 denoted Tg(zgata1:g6pdM1315-1443-egfp). Functional analysis showed that Tg(zgata1:g6pdM1315-1443-egfp) transgenic zebrafish demonstrate a decrease in g6pd activity, reduced GSH levels and hemoglobin content, and increases in pericardial edema in response to α-naphthol exposure, similar to human subjects with G6PD deficiency. We detected no other significant phenotypic abnormalities compared to controls. Taken together, these observations indicate that the Tg(zgata1:g6pdM1315-1443-egfp) zebrafish line mirrors key clinical manifestations of G6PD deficiency in humans. This model may facilitate mechanistic studies and promote translational research related to G6PD deficiency.

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Late-Life Presentation of Unsuspected G6PD Deficiency

Case Reports in Critical Care ◽

10.1155/2018/8198565 ◽

2018 ◽

Vol 2018 ◽

pp. 1-3

Author(s):

Marcos Benchimol ◽

Laura Bernardo Madeira ◽

Ricardo de Oliveira-Souza

Keyword(s):

G6pd Deficiency ◽

Clinical Manifestations ◽

Diagnostic Challenge ◽

Packed Red Blood Cells ◽

Wide Range ◽

Hemolytic Crisis ◽

History Of ◽

Triggering Conditions ◽

Red Blood Cell Count ◽

Glucose 6 Phosphate Dehydrogenase

Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is the commonest enzyme deficiency in humans with a wide range of possible clinical manifestations depending on the specific genetic variant in each case. Here we present the case of an 86-year-old male of African descent who acutely developed symptoms of G6PD deficiency immediately after he received methylene blue for treating methemoglobinemia. The contrast between a low SO2 on pulse oximetry and a normal arterial gas sampling raised the possibility of methemoglobinemia. The patient was treated with packed red blood cells and folic acid, and a rapid clinical improvement followed by normalization of the red blood cell count ensued. In view of the patient’s advanced age, the lack of a history of similar episodes in the past, and the normal laboratory results during the hemolytic crisis, this case remained a diagnostic challenge for over three months, when a follow-up measure of G6DP activity eventually confirmed the diagnosis. A latent deficiency of G6PD may become clinically manifest under the appropriate triggering conditions even in elderly patients and in the absence of past or current clinical and laboratory evidence of G6PD deficiency.

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Molecular Characterization of Glucose-6-Phosphate Dehydrogenase Deficiency in the Shenzhen Population

Human Heredity ◽

10.1159/000516808 ◽

2021 ◽

pp. 1-7

Author(s):

Jian Gao ◽

Sheng Lin ◽

Shiguo Chen ◽

Qunyan Wu ◽

Kaifeng Zheng ◽

...

Keyword(s):

G6pd Deficiency ◽

Amplification Refractory Mutation System ◽

Gene Variants ◽

Coding Region ◽

G6pd Gene ◽

Mutation System ◽

Hotspot Mutations ◽

Glucose 6 Phosphate Dehydrogenase ◽

Generation Sequencing

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is caused by one or more mutations in the G6PD gene on chromosome X. This study aimed to characterize the G6PD gene variant distribution in Shenzhen of Guangdong province. Methods: A total of 33,562 individuals were selected at the hospital for retrospective analysis, of which 1,213 cases with enzymatic activity-confirmed G6PD deficiency were screened for G6PD gene variants. Amplification refractory mutation system PCR was first used to screen the 6 dominant mutants in the Chinese population (c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.392G>T, and c.871G>A). If the 6 hotspot variants were not found, next-generation sequencing was then performed. Finally, Sanger sequencing was used to verify all the mutations. Results: The incidence of G6PD deficiency in this study was 3.54%. A total of 26 kinds of mutants were found in the coding region, except for c.-8-624T>C, which was in the noncoding region. c.1376G>T and c.1388G>A, both located in exon 12, were the top 2 mutants, accounting for 68.43% of all individuals. The 6 hotspot mutations had a cumulative proportion of 94.02%. Conclusions: This study provided detailed characteristics of G6PD gene variants in Shenzhen, and the results would be valuable to enrich the knowledge of G6PD deficiency.

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Molecular Epidemiology of G6PD Genotypes in Different Ethnic Groups Residing in Saharan and Sahelian Zones of Mauritania

Pathogens ◽

10.3390/pathogens10080931 ◽

2021 ◽

Vol 10 (8) ◽

pp. 931

Author(s):

Oum Kelthoum Mamadou Djigo ◽

Mohamed Salem Ould Ahmedou Salem ◽

Sileye Mamadou Diallo ◽

Mohamed Abdallahi Bollahi ◽

Boushab Mohamed Boushab ◽

...

Keyword(s):

G6pd Deficiency ◽

African Ancestry ◽

Population Based ◽

Black African ◽

Plasmodium Vivax Malaria ◽

The Mediterranean ◽

Linguistic Groups ◽

Study Sites ◽

Glucose 6 Phosphate Dehydrogenase ◽

Genotype Screening

Plasmodium vivax malaria is endemic in Mauritania. Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop acute hemolytic anemia when exposed to 8-aminoquinoline antimalarial drugs, which are indispensable for a complete cure. The prevalence of G6PD allelic variants was assessed in different ethno-linguistic groups present in Mauritania. A total of 996 blood samples (447 males and 549 females; 499 white Moors and 497 individuals of black African ancestry) were collected from febrile patients in 6 different study sites: Aleg, Atar, Kiffa, Kobeni, Nouakchott, and Rosso. The presence of the African-type G6PD A- (G202A, A376G, A542T, G680T, and T968C mutations) and the Mediterranean-type G6PD B- (C563T) variants was assessed by PCR followed by restriction fragment length polymorphism and/or DNA sequencing. The prevalence of African-type G6PD A- genotype was 3.6% (36/996), with 6.3% (28/447) of hemizygote (A-) males and 1.5% (8/549) of homozygous (A-A-) females. Forty of 549 (7.3%) women were heterozygous (AA-). The following genotypes were observed among hemizygous men and/or homozygous women: A376G/G202A (22/996; 2.2%), A376G/T968C Betica-Selma (12/996; 1.2%), and A376G/A542T Santamaria (2/996; 0.2%). The Mediterranean-type G6PD B- genotype was not observed. The prevalence rates of G6PD A- genotype in male (10/243; 4.1%) and heterozygous female (6/256; 2.3%) white Moors were lower (p < 0.05) than those of males (18/204; 8.8%) and heterozygous females (34/293; 11.6%) of black African ancestry. There were only a few homozygous women among both white Moors (3/256; 1.2%) and those of black African ancestry (5/293; 1.7%). The prevalence of G6PD deficiency in Mauritania was comparable to that of neighboring countries in the Maghreb. Because of the purportedly close ethnic ties between the Mauritanian white Moors and the peoples in the Maghreb, further investigations on the possible existence of the Mediterranean-type allele are required. Moreover, a surveillance system of G6PD phenotype and/or genotype screening is warranted to establish and monitor a population-based prevalence of G6PD deficiency.

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