Genetic cause for congenital methemoglobinemia in an Australian Pomeranian dog

Abstract

Little is known about genetic causes of congenital methemoglobinemia in dogs. Here, we report a CYB5R3 mutation in a Pomeranian dog with congenital methemoglobinemia. A 6‐year‐old neutered female Pomeranian dog was investigated for cyanosis noticed during anesthesia for an orthopedic procedure. The history included lifelong mild exercise intolerance and bluish tongue. Methemoglobinemia was diagnosed using co‐oximetry. The CYB5R3 gene was analyzed by comparing the patient's genomic DNA with the reference canine sequence. Mutation functional significance was investigated using snpEff and multispecies protein homology analyses. A homozygous missense single nucleotide CYB5R3 mutation (ATC ➔ CTC at codon 194) caused a p.Ile194Leu substitution. The pIle194 residue is highly conserved in other mammals, supporting the likely pathogenicity of the substitution. The mutation described here is identical to that associated with familial methemoglobinemia in a family of Japanese Pomeranian dogs. This observation, together with the homozygous mutation found in our case, indicates that the mutant allele may be widespread within the Pomeranian breed internationally.

Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs

“…The Arg219Pro missense variant seen in pit bull terriers and mixed-breed dogs was associated with similarly low QOL scores, but higher MetHb concentrations, and lower CYB5R enzyme activities compared to the Ile194Leu substitution seen in Pomeranians and at least two other small dog breeds. www.nature.com/scientificreports/ Two novel missense variants in addition to two previously reported variants in the CYB5R3 gene were identified among 30 dogs with persistent methemoglobinemia due to CYB5R deficiency 6,11,12 . Two variants were clearly breed-associated: pit bull terriers carried at least one copy of the Arg219Pro variant, while all Pomeranians, as previously reported 11,12 , and other breeds were homozygous for the Ile194Leu variant.…”

Characterization of a novel nicotinamide adenine dinucleotide-cytochrome b5 reductase mutation associated with canine hereditary methemoglobinemia

“…The same mutation allele was found in a Pomeranian dog in Australia [27]. This variant resulted in the replacement of an isoleucine (Ile) residue with leucine (Leu) at amino acid position 194 (p.Ile194Leu) [17].…”

Clinical, metabolic, and genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in cats

“…In addition, alterations in CYB5 function associated with methemoglobinemia are rarely reported in people and has not been reported in cats but has been identified in 1 dog . Close to 60 different variants likely cause CYB5R deficiency in people, while only 2 causal variants have been identified in dogs and 1 in a cat . Recently, 2 homozygous missense variants, an exon 2 (Phe36Leu) and exon 6 (Tyr179His) missense, in CYB5R3 were identified in 1 random bred cat from Japan (annotated using human sequence [NM_001171661]) .…”

“…Methemoglobinemia can be acquired or have a hereditary cause. Hereditary methemoglobinemia in dogs and cats, like people, is most commonly caused by CYB5R deficiency. Both cats of this report had markedly reduced CYB5R activity in their erythrocytes.…”