{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:40:33Z","timestamp":1770745233768,"version":"3.49.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":2531,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T00:00:00Z","timestamp":1550102400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 \u2794 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.<\/jats:p>","DOI":"10.1111\/jvim.15435","type":"journal-article","created":{"date-parts":[[2019,2,15]],"date-time":"2019-02-15T00:01:02Z","timestamp":1550188862000},"page":"868-873","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Genetic cause for congenital methemoglobinemia in an Australian Pomeranian dog"],"prefix":"10.1093","volume":"33","author":[{"given":"Shijia","family":"Zhou","sequence":"first","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide , Roseworthy, South Australia,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rick","family":"Tearle","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide , Roseworthy, South Australia,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raziallah Jafari","family":"Jozani","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide , Roseworthy, South Australia,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bethany","family":"Winra","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide , Roseworthy, South Australia,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olaf","family":"Schaaf","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide , Roseworthy, South Australia,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Nicholson","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide , Roseworthy, South Australia,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7501-2415","authenticated-orcid":false,"given":"Anne","family":"Peaston","sequence":"additional","affiliation":[{"name":"School of Animal and Veterinary Sciences, The University of Adelaide , Roseworthy, South Australia,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,3,1]]},"reference":[{"key":"2026020922230338900_jvim15435-bib-0001","doi-asserted-by":"crossref","first-page":"33","DOI":"10.5326\/15473317-35-1-33","article-title":"Cyanosis and congenital methemoglobinemia in a puppy","volume":"35","author":"Fine","year":"1999","journal-title":"J Am Anim Hosp Assoc"},{"key":"2026020922230338900_jvim15435-bib-0002","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/S0196-0644(99)70167-8","article-title":"Methemoglobinemia: etiology, pharmacology, and clinical management","volume":"34","author":"Wright","year":"1999","journal-title":"Ann Emerg Med"},{"key":"2026020922230338900_jvim15435-bib-0003","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1002\/ajh.20738","article-title":"Methemoglobin\u2013it's not just blue: a concise review","volume":"82","author":"Umbreit","year":"2007","journal-title":"Am J Hematol"},{"key":"2026020922230338900_jvim15435-bib-0004","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/03630269809071512","article-title":"DNA sequence analysis proves Hb M-Milwaukee-2 is due to beta-globin gene codon 92 (CAC\u2013&gt;TAC), the presumed mutation of Hb M-Hyde Park and Hb M-Akita","volume":"22","author":"Hutt","year":"1998","journal-title":"Hemoglobin"},{"key":"2026020922230338900_jvim15435-bib-0005","first-page":"267","article-title":"Hemoglobin Hana or alpha 2 beta 2 63 (E7) His-Asn: a new unstable hemoglobin variant with a paradoxically different clinical manifestations in smokers and non-smokers in the same family","volume":"43","author":"Divoky","year":"1997","journal-title":"Vnitr Lek"},{"key":"2026020922230338900_jvim15435-bib-0006","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1590\/S1415-47572010005000058","article-title":"Familial congenital cyanosis caused by Hb-M(Yantai)(alpha-76 GAC \u2013&gt; TAC, Asp \u2013&gt; Tyr)","volume":"33","author":"Sun","year":"2010","journal-title":"Genet Mol Biol"},{"key":"2026020922230338900_jvim15435-bib-0007","first-page":"1","article-title":"Congenital methemoglobinemia due to Hb F-M-Fort Ripley in a preterm newborn","author":"Ghotra","year":"2016","journal-title":"BMJ Case Rep"},{"issue":"2","key":"2026020922230338900_jvim15435-bib-0008","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1111\/jvim.12423","article-title":"Congenital methemoglobinemia in a dog with a promoter deletion and a nonsynonymous coding variant in the gene encoding cytochrome b","volume":"28","author":"McKenna","year":"2014","journal-title":"J Vet Intern Med"},{"key":"2026020922230338900_jvim15435-bib-0009","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/jvim.15031","article-title":"Familial Congenital Methemoglobinemia in Pomeranian Dogs Caused by a Missense Variant in the NADH-Cytochrome B5 Reductase Gene","volume":"32","author":"Shino","year":"2018","journal-title":"J Vet Intern Med"},{"key":"2026020922230338900_jvim15435-bib-0010","first-page":"283","article-title":"Textbook of Veterinary Internal Medicine","author":"Allen","year":"2009","edition":"7"},{"key":"2026020922230338900_jvim15435-bib-0011","first-page":"96","article-title":"Small Animal Internal Medicine, 5th ed","author":"Ware","year":"2014"},{"key":"2026020922230338900_jvim15435-bib-0012","first-page":"471","article-title":"Pathologic Basis of Veterinary Disease Expert Consult\u2014E-BOOK","author":"L\u00f3pez","year":"2016"},{"key":"2026020922230338900_jvim15435-bib-0013","first-page":"279","article-title":"Textbook of Veterinary Internal Medicine","author":"Giger","year":"2009","edition":"7"},{"key":"2026020922230338900_jvim15435-bib-0014","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"Li","year":"2010","journal-title":"Bioinformatics"},{"key":"2026020922230338900_jvim15435-bib-0015","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res"},{"key":"2026020922230338900_jvim15435-bib-0016","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w(1118); iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"2026020922230338900_jvim15435-bib-0017","doi-asserted-by":"crossref","first-page":"D733","DOI":"10.1093\/nar\/gkv1189","article-title":"Reference sequence (RefSeq) database at NCBI: Current, Canis lupus familiaris, and functional annotation release 105","volume":"44","author":"O'Leary","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2026020922230338900_jvim15435-bib-0018","doi-asserted-by":"crossref","first-page":"3389","DOI":"10.1093\/nar\/25.17.3389","article-title":"Gapped BLAST and PSI-BLAST: a new generation of protein database search programs","volume":"25","author":"Altschul","year":"1997","journal-title":"Nucleic Acids Res"},{"key":"2026020922230338900_jvim15435-bib-0019","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1042\/bj3550529","article-title":"Transcriptional and translational mechanisms of cytochrome b5 reductase isoenzyme generation in humans","volume":"355","author":"Leroux","year":"2001","journal-title":"Biochem J"},{"key":"2026020922230338900_jvim15435-bib-0020","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.abb.2006.04.021","article-title":"Expression and characterization of a functional canine variant of cytochrome b5 reductase","volume":"452","author":"Roma","year":"2006","journal-title":"Arch Biochem Biophys"},{"key":"2026020922230338900_jvim15435-bib-0021","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1182\/blood.V92.1.310.413k24_310_319","article-title":"An erythroid-specific transcript generates the soluble form of NADH-cytochrome b5 reductase in humans","volume":"92","author":"Bulbarelli","year":"1998","journal-title":"Blood"},{"key":"2026020922230338900_jvim15435-bib-0022","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.4161\/auto.29197","article-title":"PRKAA1\/AMPK\u03b11 is required for autophagy-dependent mitochondrial clearance during erythrocyte maturation","volume":"10","author":"Zhu","year":"2014","journal-title":"Autophagy"},{"key":"2026020922230338900_jvim15435-bib-0023","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1021\/bi501198f","article-title":"A conservative lsoleucine to leucine mutation causes major rearrangements and cold sensitivity in KlenTaq1 DNA polymerase","volume":"54","author":"Wu","year":"2015","journal-title":"Biochemistry"},{"key":"2026020922230338900_jvim15435-bib-0024","doi-asserted-by":"crossref","first-page":"3656","DOI":"10.1016\/j.jmb.2014.08.018","article-title":"A conserved isoleucine maintains the inactive state of Bruton's tyrosine kinase","volume":"426","author":"Boyken","year":"2014","journal-title":"J Mol Biol"},{"key":"2026020922230338900_jvim15435-bib-0025","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.abb.2017.08.015","article-title":"Effect of conservative mutations (L94V and L94I) on the structure and stability of horse cytochrome c","volume":"633","author":"Khan","year":"2017","journal-title":"Arch Biochem Biophys"},{"key":"2026020922230338900_jvim15435-bib-0026","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1038\/ng.3658","article-title":"Unsupervised detection of cancer driver mutations with parsimony-guided learning","volume":"48","author":"Kumar","year":"2016","journal-title":"Nat Genet"},{"key":"2026020922230338900_jvim15435-bib-0027","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1111\/jvim.14843","article-title":"Long-term treatment with methylene blue in a dog with hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency","volume":"31","author":"Jaffey","year":"2017","journal-title":"J Vet Intern Med"}],"container-title":["Journal of Veterinary Internal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjvim.15435","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jvim.15435","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jvim.15435","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jvim\/article-pdf\/33\/2\/868\/66659311\/jvim15435.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jvim\/article-pdf\/33\/2\/868\/66659311\/jvim15435.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T03:35:05Z","timestamp":1770694505000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jvim\/article\/33\/2\/868\/8448056"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,1]]},"references-count":27,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,3,1]]}},"URL":"https:\/\/doi.org\/10.1111\/jvim.15435","relation":{},"ISSN":["1939-1676"],"issn-type":[{"value":"1939-1676","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,3]]},"published":{"date-parts":[[2019,3,1]]},"assertion":[{"value":"2018-09-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-02-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}