Characterization of a novel nicotinamide adenine dinucleotide-cytochrome b5          reductase mutation associated with canine hereditary methemoglobinemia

Otsuka-Yamasaki, Yayoi; Inanami, Osamu; Shino, Haruka; Sato, Ryo; Yamasaki, Masahiro

doi:10.1292/jvms.20-0390

Cited by 2 publications

(2 citation statements)

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“…Four different missense variants in the CYB5R3 gene have been reported to be causative for type I RCM in dogs [ 18 , 20 , 21 , 38 ]. The CYB5R3 missense variant p.I194L was found in several Pomeranians worldwide, while the p.R219P missense variant was seen in several Pit Bull terriers in North America; however, their actual prevalence remains to be determined [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…It was a bone fracture that brought the affected cat of this report to the clinic, where the cyanosis was recognized during induction of anesthesia. Likewise, severe methemoglobinemia has been reported in CYB5R3-deficient dogs [ 14 , 15 , 16 , 17 , 18 , 20 , 21 , 38 ] and humans [ 5 , 9 ]. However, while the increase in methemoglobin levels above 50% may lead to seizures and even death in human patients [ 9 ], dogs, and cats with CYB5R3 deficiency appear more tolerant to such a massive loss of O 2 carrying capacity [ 14 , 18 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

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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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