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Clinical, metabolic, and genetic characterization of hereditary methemoglobinemia caused by cytochrome b 5 reductase deficiency in cats

2019; Wiley; Volume: 33; Issue: 6 Linguagem: Inglês

10.1111/jvim.15637

1939-1676

Jared A. Jaffey, N. Scott Reading, Urs Giger, Osheiza Abdulmalik, R. M. Buckley, Sophie Johnstone, Ronald H. L. Li,

Erythrocyte Function and Pathophysiology

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.