Clinical, metabolic, and genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in cats

J Vet Intern Med. 2019 Nov;33(6):2725-2731. doi: 10.1111/jvim.15637. Epub 2019 Oct 25.


Two non-pedigreed male castrated cats had persistent cyanosis over a 3-year observation period. Clinical cardiopulmonary evaluations did not reveal abnormalities, but the blood remained dark after exposure to air. Erythrocytic methemoglobin concentrations were high (~40% of hemoglobin) and cytochrome b5 reductase (CYB5R) activities in erythrocytes were low (≤15% of control). One cat remained intolerant of exertion, and the other cat developed anemia and died due to an unidentified comorbidity. Whole-genome sequencing revealed a homozygous c.625G>A missense variant (B4:137967506) and a c.232-1G>C splice acceptor variant (B4:137970815) in CYB5R3, respectively, which were absent in 193 unaffected additional cats. The p.Gly209Ser missense variant likely disrupts a nicotinamide adenine dinucleotide (NADH)-binding domain, while the splicing error occurs at the acceptor site for exon 4, which likely affects downstream translation of the protein. The 2 novel CYB5R3 variants were associated with methemoglobinemia using clinical, biochemical, genomics, and in silico protein studies. The variant prevalence is unknown in the cat population.

Keywords: CYB5R3; cyanosis; cytochrome b5 reductase; methylene blue; whole-genome sequencing.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cat Diseases / genetics
  • Cat Diseases / pathology*
  • Cats
  • Cytochromes b5 / deficiency*
  • Cytochromes b5 / genetics
  • Fatal Outcome
  • Genetic Predisposition to Disease*
  • Male
  • Methemoglobinemia / genetics
  • Methemoglobinemia / veterinary*
  • Mutation


  • Cytochromes b5