In other species: dog

Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 250800 (trait) , 613213 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009606: methemoglobinemia due to deficiency of methemoglobin reductase

Single-gene trait/disorder: yes

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Cross-species summary: Methemoglobinemia

Species-specific description: see also 'OMIA:001171-9685 : Methaemoglobinaemia, generic in Felis catus'

Molecular basis: Jaffey et al. (2019): "Whole‐genome sequencing revealed a homozygous c.625G>A missense variant (B4:137967506) [omia.variant:1155] and a c.232‐1G>C splice acceptor variant (B4:137970815) [omia.variant:1156] in CYB5R3, [one in each of two affected cats] 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."
Jenni et al. (2023): "Genetic analyses [of an affected European domestic shorthair cat] revealed a single homozygous base exchange at the beginning of intron 3 of the CYB5R3 gene, c.226+5G>A [omia.variant:1548]. Subsequent mRNA studies confirmed a splice defect and demonstrated expression of two mutant CYB5R3 transcripts. ... Sequence analysis revealed that mut #1 contained an insertion of 36 bp derived from the beginning of intron 3, XM_045062469.1:r.226_227insGTGAGCGCAGCCCTGACCCA-GCCCGAGTGGAACCGG ... . Mut #2 lacked 73 nucleotides comprising the entire exon 3, XM_045062469.1:r.154_226del73 ... . In mut #1, the 36 bp insertion maintained the reading frame but is predicted to insert 12 amino acids into the protein XP_044918404.1:p.(G76_Q77insERSPDPARVEPG). The inserted amino acids are predicted to form an additional loop between the FAD and NADH binding domains ... . In mut #2, the exon skipping results in an early premature stop codon, XP_044918404.1:p.(V52Afs*58), truncating 64% of the wildtype open reading frame."

Clinical features: Jenni et al. (2023): "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. ... 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. "

Breed: Domestic Shorthair (Cat) (VBO_0100119).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: