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

Abstract Genotype–phenotype correlations of humans and dogs with hereditary methemoglobinemia are not yet well characterized. We determined total hemoglobin and methemoglobin (MetHb) concentrations, cytochrome b5 reductase (CYB5R) enzyme activities, genotypes, and clinical signs in 30 dogs with pers...

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Autores principales:	J. A. Jaffey, N. S. Reading, O. Abdulmalik, R. Kreisler, G. Bullock, A. Wiest, N. A. Villani, T. Mhlanga-Mutangadura, G. S. Johnson, L. A. Cohn, N. Isaza, J. W. Harvey, U. Giger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7cae2504745c40369b98997a367c89ae
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spelling	oai:doaj.org-article:7cae2504745c40369b98997a367c89ae2021-12-02T15:11:49ZClinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs10.1038/s41598-020-78391-22045-2322https://doaj.org/article/7cae2504745c40369b98997a367c89ae2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78391-2https://doaj.org/toc/2045-2322Abstract Genotype–phenotype correlations of humans and dogs with hereditary methemoglobinemia are not yet well characterized. We determined total hemoglobin and methemoglobin (MetHb) concentrations, cytochrome b5 reductase (CYB5R) enzyme activities, genotypes, and clinical signs in 30 dogs with persistent cyanosis without cardiopulmonary disease. Erythrocytic CYB5R enzyme activities were low in all dogs assayed. Owner-reported quality of life ranged from subclinical to occasional exertional syncope. Two previously reported and two novel CYB5R3 missense variants were identified among the methemoglobinemic cohort and were predicted to impair enzyme function. Two variants were recurrent: a homozygous Ile194Leu substitution was found in Pomeranians and other small dogs, and a homozygous Arg219Pro change occurred predominately in pit bull terriers. The other two variants were Thr202Ala and Gly76Ser substitutions in single dogs. Of the two common CYB5R3 genotypes, Arg219Pro was associated with a more severe metabolic phenotype. We conclude that CYB5R3 deficiency is the predominate cause of canine hereditary methemoglobinemia. Although this finding is unlikely to alter the clinical approach to hereditary methemoglobinemia in dogs, it demonstrates the possibility of how genotype–phenotype cohort analysis might facilitate precision medicine in the future in veterinary medicine.J. A. JaffeyN. S. ReadingO. AbdulmalikR. KreislerG. BullockA. WiestN. A. VillaniT. Mhlanga-MutangaduraG. S. JohnsonL. A. CohnN. IsazaJ. W. HarveyU. GigerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-9 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q J. A. Jaffey N. S. Reading O. Abdulmalik R. Kreisler G. Bullock A. Wiest N. A. Villani T. Mhlanga-Mutangadura G. S. Johnson L. A. Cohn N. Isaza J. W. Harvey U. Giger Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs
description	Abstract Genotype–phenotype correlations of humans and dogs with hereditary methemoglobinemia are not yet well characterized. We determined total hemoglobin and methemoglobin (MetHb) concentrations, cytochrome b5 reductase (CYB5R) enzyme activities, genotypes, and clinical signs in 30 dogs with persistent cyanosis without cardiopulmonary disease. Erythrocytic CYB5R enzyme activities were low in all dogs assayed. Owner-reported quality of life ranged from subclinical to occasional exertional syncope. Two previously reported and two novel CYB5R3 missense variants were identified among the methemoglobinemic cohort and were predicted to impair enzyme function. Two variants were recurrent: a homozygous Ile194Leu substitution was found in Pomeranians and other small dogs, and a homozygous Arg219Pro change occurred predominately in pit bull terriers. The other two variants were Thr202Ala and Gly76Ser substitutions in single dogs. Of the two common CYB5R3 genotypes, Arg219Pro was associated with a more severe metabolic phenotype. We conclude that CYB5R3 deficiency is the predominate cause of canine hereditary methemoglobinemia. Although this finding is unlikely to alter the clinical approach to hereditary methemoglobinemia in dogs, it demonstrates the possibility of how genotype–phenotype cohort analysis might facilitate precision medicine in the future in veterinary medicine.
format	article
author	J. A. Jaffey N. S. Reading O. Abdulmalik R. Kreisler G. Bullock A. Wiest N. A. Villani T. Mhlanga-Mutangadura G. S. Johnson L. A. Cohn N. Isaza J. W. Harvey U. Giger
author_facet	J. A. Jaffey N. S. Reading O. Abdulmalik R. Kreisler G. Bullock A. Wiest N. A. Villani T. Mhlanga-Mutangadura G. S. Johnson L. A. Cohn N. Isaza J. W. Harvey U. Giger
author_sort	J. A. Jaffey
title	Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs
title_short	Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs
title_full	Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs
title_fullStr	Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs
title_full_unstemmed	Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs
title_sort	clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/7cae2504745c40369b98997a367c89ae
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Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs

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