OMIA 002131-9615 : Methemoglobinaemia, CYB5R3-related in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s) (MIM number): 250800

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

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."

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CYB5R3 cytochrome b5 reductase 3 Canis lupus familiaris 10 NC_006592.3 (22829898..22848284) CYB5R3 Homologene, Ensembl, NCBI gene

Variants

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.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Pomeranian Methemoglobinaemia, CYB5R3-related CYB5R3 missense CanFam3.1 c.580A>C p.Ile194Leu 2018 29356095
Mixed breed Methemoglobinaemia, CYB5R3-related CYB5R3 missense CanFam3.1 10 g.22832963G>A c.214G>A p.Gly72Ser 2017 28963729 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

References


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.
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