OMIA:002131-9615 : Methaemoglobinaemia, CYB5R3-related in Canis lupus familiaris (dog)

In other species: domestic cat

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:

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2017

Cross-species summary: Methemoglobinemia

Molecular basis: Analysis of genome sequence in two comparative candidate genes in a single affected dog enabled Jaffey et al. (2017) to report that "No potentially causal sequence variants were recognized within the CYB5A genic region but, we found 2 heterozygous CYB5R3 missense mutations: [CanFam3.1] chr10:22,832,963G>A that predicted a CYB5R3:p.Gly72Ser amino acid substitution and [CanFam3.1] chr10:22,836,951A>C that predicted a CYB5R3:p.Ile190Leu amino acid substitution. . . . There is strong indirect evidence for a causal contribution from 1 of them: CYB5R3:p.Gly72Ser. Indeed, 3 on-line algorithms that estimate the functional consequences of sequence variants all predict impaired function for the Ser72 allele . . . . In addition, a heterozygous glycine-to-serine missense mutation at a homologous position in human cytochrome b5 reductase was reported to be partially responsible for the methemoglobinemia in a compound heterozygous human patient. . . . However, a single heterozygous mutation cannot by itself be responsible for an autosomal recessive disease such as cytochrome b5 reductase deficiency." In summary, Jaffey et al. (2017) have proposed that this case could be due to compound heterozygosity involving one unquestionably deleterious variant, but expression studies and population-wide associations studies have yet to be conducted. Compound heterozygosity as a cause of inherited disorders is not uncommon in humans, e.g. the OMIM entry (see above hyperlink) mentions that some cases of this disorder in humans are due to "compound heterozygous mutation[s] in the CYB5R3 gene". Shino et al. (2018) reported a likely causal variant in Pomeranians, namely c.580A>C; p.Ile194Leu. But the evidence supporting the causality of this variant is marginal, comprising an affected sire and his two affected offspring being homozygous for the C variant, with 5 unrelated normal Pomeranians and some normal Beagles being homozygous for the A variant.

Clinical features: Jaffey et al. (2017): "Arterial blood gas analysis with co-oximetry identified methemoglobinemia concurrent with normal arterial oxygen tension at FIO2 = 0.21, which supported a nonrespiratory cause for cyanosis, tachypnea, and exercise intolerance."

Breed: Pomeranian (Dog) (VBO_0201043).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CYB5R3 cytochrome b5 reductase 3 Canis lupus familiaris 10 NC_051814.1 (23565239..23592996) CYB5R3 Homologene, Ensembl , NCBI gene


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
850 Mixed Breed (Dog) Methemoglobinaemia, CYB5R3-related CYB5R3 missense Naturally occurring variant CanFam3.1 10 g.22832963G>A c.214G>A p.(G72S) 2017 28963729 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool
967 Pomeranian (Dog) Methemoglobinaemia, CYB5R3-related CYB5R3 missense Naturally occurring variant CanFam3.1 10 g.22836951A>C c.580A>C p.(I194L) NM_001048084.1, NP_001041549.1 2018 29356095 Genomic coordinates in CanFam3.1 provided by Zoe Shmidt and Robert Kuhn.

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2022). OMIA:002131-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset].


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.

2023 Meadows, J.R.S., Kidd, J.M., Wang, G.D., Parker, H.G., Schall, P.Z., Bianchi, M., Christmas, M.J., Bougiouri, K., Buckley, R.M., Hitte, C., Nguyen, A.K., Wang, C., Jagannathan, V., Niskanen, J.E., Frantz, L.A.F., Arumilli, M., Hundi, S., Lindblad-Toh, K., Ginja, C., Agustina, K.K., André, C., Boyko, A.R., Davis, B.W., Drögemüller, M., Feng, X.Y., Gkagkavouzis, K., Iliopoulos, G., Harris, A.C., Hytönen, M.K., Kalthoff, D.C., Liu, Y.H., Lymberakis, P., Poulakakis, N., Pires, A.E., Racimo, F., Ramos-Almodovar, F., Savolainen, P., Venetsani, S., Tammen, I., Triantafyllidis, A., vonHoldt, B., Wayne, R.K., Larson, G., Nicholas, F.W., Lohi, H., Leeb, T., Zhang, Y.P., Ostrander, E.A. :
Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture. Genome Biol 24:187, 2023. Pubmed reference: 37582787. DOI: 10.1186/s13059-023-03023-7.
2022 Jaffey, J.A., Struthers, J.D., Yuh, E.L., Hostnik, E.T., Runyan, R.A., Reading, N.S. :
Oral methylene blue treatment in a dog with cytochrome B5 reductase deficiency and 78, XX testicular disorder of sex development. Top Companion Anim Med 49:100649, 2022. Pubmed reference: 35202847. DOI: 10.1016/j.tcam.2022.100649.
2021 Otsuka-Yamasaki, Y., Inanami, O., Shino, H., Sato, R., Yamasaki, M. :
Characterization of a novel nicotinamide adenine dinucleotide-cytochrome b5 reductase mutation associated with canine hereditary methemoglobinemia. J Vet Med Sci 83:315-321, 2021. Pubmed reference: 33342963. DOI: 10.1292/jvms.20-0390.
2018 Shino, H., Otsuka-Yamasaki, Y., Sato, T., Ooi, K., Inanami, O., Sato, R., Yamasaki, M. :
Familial congenital methemoglobinemia in Pomeranian dogs caused by a missense variant in the NADH-cytochrome B5 reductase gene. J Vet Intern Med 32:165-171, 2018. Pubmed reference: 29356095. DOI: 10.1111/jvim.15031.
2017 Jaffey, J.A., Harmon, M.R., Villani, N.A., Creighton, E.K., Johnson, G.S., Giger, U., Dodam, J.R. :
Long-term treatment with methylene blue in a dog with hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency. J Vet Intern Med , 2017. Pubmed reference: 28963729. DOI: 10.1111/jvim.14843.

Edit History

  • Created by Frank Nicholas on 21 Oct 2017
  • Changed by Frank Nicholas on 21 Oct 2017
  • Changed by Frank Nicholas on 23 Oct 2017
  • Changed by Frank Nicholas on 02 Feb 2018
  • Changed by Imke Tammen2 on 06 Aug 2021
  • Changed by Imke Tammen2 on 11 Sep 2022