Preliminary data were presented at the ACVIM Forum 2011 in Denver, CO: Inal Gultekin G, Raj K, Lehman S, Manhart K, Giger U. Survey of erythrocytic pyruvate kinase deficiency in dogs. J Vet Intern Med 2011;25 : 702. (Abstract) and the 6th International Canine and Feline Genome Conference, Visby, Sweden
Erythrocytic Pyruvate Kinase Mutations Causing Hemolytic Anemia, Osteosclerosis, and Secondary Hemochromatosis in Dogs
Version of Record online: 13 JUL 2012
Copyright © 2012 by the American College of Veterinary Internal Medicine
Journal of Veterinary Internal Medicine
Volume 26, Issue 4, pages 935–944, July-August 2012
How to Cite
Inal Gultekin, G., Raj, K., Foureman, P., Lehman, S., Manhart, K., Abdulmalik, O. and Giger, U. (2012), Erythrocytic Pyruvate Kinase Mutations Causing Hemolytic Anemia, Osteosclerosis, and Secondary Hemochromatosis in Dogs. Journal of Veterinary Internal Medicine, 26: 935–944. doi: 10.1111/j.1939-1676.2012.00958.x
- Issue online: 13 JUL 2012
- Version of Record online: 13 JUL 2012
- Manuscript Accepted: 8 MAY 2012
- Manuscript Revised: 29 MAR 2012
- Manuscript Received: 4 NOV 2011
- National Institutes of Health. Grant Number: RR002512 and HL103186
- Hereditary Disorders;
Erythrocytic pyruvate kinase (PK) deficiency, first documented in Basenjis, is the most common inherited erythroenzymopathy in dogs.
To report 3 new breed-specific PK-LR gene mutations and a retrospective survey of PK mutations in a small and selected group of Beagles and West Highland White Terriers (WHWT).
Labrador Retrievers (2 siblings, 5 unrelated), Pugs (2 siblings, 1 unrelated), Beagles (39 anemic, 29 other), WHWTs (22 anemic, 226 nonanemic), Cairn Terrier (n = 1).
Exons of the PK-LR gene were sequenced from genomic DNA of young dogs (<2 years) with persistent highly regenerative hemolytic anemia.
A nonsense mutation (c.799C>T) resulting in a premature stop codon was identified in anemic Labrador Retriever siblings that had osteosclerosis, high serum ferritin concentrations, and severe hepatic secondary hemochromatosis. Anemic Pug and Beagle revealed 2 different missense mutations (c.848T>C, c.994G>A, respectively) resulting in intolerable amino acid changes to protein structure and enzyme function. Breed-specific mutation tests were developed. Among the biased group of 248 WHWTs, 9% and 35% were homozygous (affected) and heterozygous, respectively, for the previously described mutation (mutant allele frequency 0.26). A PK-deficient Cairn Terrier had the same insertion mutation as the affected WHWTs. Of the selected group of 68 Beagles, 35% were PK-deficient and 3% were carriers (0.37).
Conclusions and Clinical Importance
Erythrocytic PK deficiency is caused by different mutations in different dog breeds and causes chronic severe hemolytic anemia, hemosiderosis, and secondary hemochromatosis because of chronic hemolysis and, an as yet unexplained osteosclerosis. The newly developed breed-specific mutation assays simplify the diagnosis of PK deficiency.