Clinical, metabolic, and genetic characterization of hereditary methemoglobinemia caused by cytochrome b₅reductase deficiency in cats

Abstract

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 b 5 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. K E Y W O R D S cyanosis, CYB5R3, cytochrome b 5 reductase, methylene blue, whole-genome sequencing 1 | CAT 1 A 6-month-old castrated male domestic shorthair cat was presented to South Coastal Animal Health for evaluation of right hind limb lameness. The cat had been adopted, along with a littermate (unaffected), Abbreviations: CYB5, cytochrome b5; CYB5R, cytochrome b5 reductase; FAD, flavin adenine

Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon inCLN6

“…CLN6 variants were identified in the ∼195 cats of the 99 Lives cat whole genome sequencing project ( Jaffey et al 2019 ) ( Table 2 ). Sixteen missense, synonymous or splice region variants were identified in the WGS 99 Lives data of 195 cats, however the loss of function variant (alternative) allele identified in the proband was not present.…”

A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism

“…Once coupled with the quickly advancing sequencing technology and exploitable results, genomic medicine in companion animals promises to expand the comparative knowledge of mechanisms of action across species. Despite the continuing successful discovery of feline disease variants using both candidate gene and whole genome sequencing (WGS) approaches [1,[12][13][14][15], the understanding of normal and disease sequence variation in the domestic cat and interrogation of gene structure and function is limited by an incomplete genome assembly.…”

A Deletion in GDF7 is Associated with a Heritable Forebrain Commissural Malformation Concurrent with Ventriculomegaly and Interhemispheric Cysts in Cats

“…Overall, an extended pedigree was developed, and was expected to be sufficient for GWAS and WGS investigations for the causal variant. Furthermore, a variant dataset from WGS of domestic cats, the 99 Lives Cat Genome Sequencing Initiative, which has revealed the causative variants for several cat diseases and traits in the last several years [ 31 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], was considered to facilitate the variant filtering to find the private variants.…”