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: