OMIA:002131-9615 : Methaemoglobinaemia, CYB5R3-related in Canis lupus familiaris
In other species: domestic cat
Categories: Haematopoietic system phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 250800 (trait) , 613213 (gene)
Links to MONDO diseases:
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."
|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|
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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||Inferred EVA rsID||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||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.|
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.
|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.|
- Created by Frank Nicholas on 21 Oct 2017
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