Cytochrome b5 reductases: Redox regulators of cell homeostasis

Hall, Robert M.; Yuan, Shuai; Wood, Katherine C.; Katona, Máté; Straub, Adam C.

doi:10.1016/j.jbc.2022.102654

Cited by 29 publications

(15 citation statements)

References 144 publications

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“…The resulting amino acid substitution, Arg58Gln, was predicted to be probably damaging by PolyPhen2 ( , accessed on 31 January 2023) and damaging by SIFT ( , accessed on 31 January 2023) software. Since the variant is located in the flavin adenine dinucleotide (FAD)-binding domain, it is likely to affect binding affinity to FAD, resulting in the reduced efficiency of electron transfer ( Figure 2 ) [ 3 , 4 ].…”

Section: Case Reportmentioning

confidence: 99%

Hereditary Congenital Methemoglobinemia Diagnosed at the Age of 79 Years: A Case Report

Nakata¹,

Yokota²,

Tabata

et al. 2023

Medicina

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Background: Cardiopulmonary disorders are the most common cause of central cyanosis, and methemoglobinemia is often overlooked in the differential diagnosis of patients with central cyanosis. In most cases, methemoglobinemia is acquired and hereditary congenital methemoglobinemia is rare. Only a few case reports of congenital methemoglobinemia can be found in PubMed. To date, only four cases of congenital methemoglobinemia diagnosed after the age of 50 years have been reported. Case Presentation: A 79-year-old Japanese woman presented at our hospital with the chief complaints of dyspnea and cyanosis. She exhibited cyanosis of the lips and extremities, and her SpO2 was 80%, with oxygen administration at 5 L/min. Blood gas analysis revealed a PaO2 of 325.4 mmHg and methemoglobin level of 36.9%. The SpO2 and PaO2 values were dissociated, and methemoglobin levels were markedly elevated. Genetic analysis revealed a nonsynonymous variant in the gene encoding nicotinamide adenine dinucleotide cytochrome (NADH) B5 reductase 3 (CYB5R3), and the patient was diagnosed with congenital methemoglobinemia. Conclusions: It is important to consider methemoglobinemia in the differential diagnosis of patients with central cyanosis. At 79 years of age, our patient represents the oldest patient with this diagnosis. This report indicates that it is crucial to consider the possibility of methemoglobinemia regardless of the patient’s age.

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Section: Case Reportmentioning

confidence: 99%

Hereditary Congenital Methemoglobinemia Diagnosed at the Age of 79 Years: A Case Report

Nakata¹,

Yokota²,

Tabata

et al. 2023

Medicina

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“…Consequently, the hemoglobin is unable to convert the iron back to its ferrous state [ 4 ]. There are also mutations in the globin genes, forming various variants of hemoglobin (MetHb), stabilizing the iron in Fe +++ state [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…The CYB5R3 gene encoding cytochrome-b5 reductase 3 is involved in cellular redox and metabolic hemostasis [ 5 ]. Recently, numerous studies have determined the molecular basis of patients with methemoglobinemia.…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamic Simulation Analysis of a Novel Missense Variant in CYB5R3 Gene in Patients with Methemoglobinemia

et al. 2023

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Background and Objective: Mutations in the CYB5R3 gene cause reduced NADH-dependent cytochrome b5 reductase enzyme function and consequently lead to recessive congenital methemoglobinemia (RCM). RCM exists as RCM type I (RCM1) and RCM type II (RCM2). RCM1 leads to higher methemoglobin levels causing only cyanosis, while in RCM2, neurological complications are also present along with cyanosis. Materials and Methods: In the current study, a consanguineous Pakistani family with three individuals showing clinical manifestations of cyanosis, chest pain radiating to the left arm, dyspnea, orthopnea, and hemoptysis was studied. Following clinical assessment, a search for the causative gene was performed using whole exome sequencing (WES) and Sanger sequencing. Various variant effect prediction tools and ACMG criteria were applied to interpret the pathogenicity of the prioritized variants. Molecular dynamic simulation studies of wild and mutant systems were performed to determine the stability of the mutant CYB5R3 protein. Results: Data analysis of WES revealed a novel homozygous missense variant NM_001171660.2: c.670A > T: NP_001165131.1: p.(Ile224Phe) in exon 8 of the CYB5R3 gene located on chromosome 22q13.2. Sanger sequencing validated the segregation of the identified variant with the disease phenotype within the family. Bioinformatics prediction tools and ACMG guidelines predicted the identified variant p.(Ile224Phe) as disease-causing and likely pathogenic, respectively. Molecular dynamics study revealed that the variant p.(Ile224Phe) in the CYB5R3 resides in the NADH domain of the protein, the aberrant function of which is detrimental. Conclusions: The present study expanded the variant spectrum of the CYB5R3 gene. This will facilitate genetic counselling of the same and other similar families carrying mutations in the CYB5R3 gene.

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“…Heme groups in hemoglobin can only transport oxygen when containing iron in the ferrous state (Fe 2+ ). Oxidation of Fe 2+ to Fe 3+ converts hemoglobin to methemoglobin (metHb), which is unable to bind and transport oxygen [ 1 ]. Reduction of Fe 3+ to Fe 2+ is mainly catalyzed by the erythrocytic enzyme cytochrome b5 reductase 3 (CYB5R3) a.…”

Section: Introductionmentioning

confidence: 99%

“…Methemoglobinemia can be acquired due to exposure to oxidative agents [ 2 ] or hereditary [ 3 ]. Hereditary methemoglobinemia is most commonly due to diminished erythrocytic CYB5R activity, while low cytochrome b5 levels, abnormal hemoglobin M, or defects compromising the production of antioxidants are less common causes [ 1 , 3 , 4 , 5 ]. Persistent methemoglobinemia may also be caused by flavin adenine dinucleotide (FAD) deficiency [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Methemoglobinemia, Increased Deformability and Reduced Membrane Stability of Red Blood Cells in a Cat with a CYB5R3 Splice Defect

Jenni

Ludwig-Peisker

Jagannathan

et al. 2023

Cells

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Methemoglobinemia is an acquired or inherited condition resulting from oxidative stress or dysfunction of the NADH-cytochrome b5 reductase or associated pathways. This study describes the clinical, pathophysiological, and molecular genetic features of a cat with hereditary methemoglobinemia. Whole genome sequencing and mRNA transcript analyses were performed in affected and control cats. Co-oximetry, ektacytometry, Ellman’s assay for reduced glutathione concentrations, and CYB5R activity were assessed. A young adult European domestic shorthair cat decompensated at induction of anesthesia and was found to have persistent methemoglobinemia of 39 ± 8% (reference range < 3%) of total hemoglobin which could be reversed upon intravenous methylene blue injection. The erythrocytic CYB5R activity was 20 ± 6% of normal. Genetic analyses revealed a single homozygous base exchange at the beginning of intron 3 of the CYB5R3 gene, c.226+5G>A. Subsequent mRNA studies confirmed a splice defect and demonstrated expression of two mutant CYB5R3 transcripts. Erythrocytic glutathione levels were twice that of controls. Mild microcytosis, echinocytes, and multiple Ca2+-filled vesicles were found in the affected cat. Erythrocytes were unstable at high osmolarities although highly deformable as follows from the changes in elongation index and maximal-tolerated osmolarity. Clinicopathological presentation of this cat was similar to other cats with CYB5R3 deficiency. We found that methemoglobinemia is associated with an increase in red blood cell fragility and deformability, glutathione overload, and morphological alterations typical for stress erythropoiesis.

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Cytochrome b5 reductases: Redox regulators of cell homeostasis

Cited by 29 publications

References 144 publications

Hereditary Congenital Methemoglobinemia Diagnosed at the Age of 79 Years: A Case Report

Hereditary Congenital Methemoglobinemia Diagnosed at the Age of 79 Years: A Case Report

Molecular Dynamic Simulation Analysis of a Novel Missense Variant in CYB5R3 Gene in Patients with Methemoglobinemia

Methemoglobinemia, Increased Deformability and Reduced Membrane Stability of Red Blood Cells in a Cat with a CYB5R3 Splice Defect

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