OMIA 000844-9615 : Pyruvate kinase deficiency of erythrocyte in Canis lupus familiaris

In other species: domestic cat

Possibly relevant human trait(s) and/or gene(s) (MIM number): 266200

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1994

Cross-species summary: Also known as PK deficiency

Species-specific description: In pyruvate kinase deficiency, the erythrocyte life span is markedly reduced, which leads to severe regenerative hemolytic anemia. Clinical signs include intermittent weakness, moderate hepatosplenomegaly at less than one year of age and bone marrow and liver failure by 5 years of age. Pyruvate kinase deficiency has been identified in the basenji, beagle, West Highland white terrier, and Cairn terrier. The mode of inheritance is autosomal recessive.

Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Whitney et al. (1994) showed that the causative mutation in Basenjis is a single base-pair deletion in exon 5 of the gene encoding R-type pyruvate kinase (PKLR).

The causative mutation in West Highland white terriers is a 6 base pair insertion in exon 10 of the same gene (Skelly et al., 1999).

Gultekin et al. (2012) reported three new causative mutations in the canine PKLR gene: a nonsense mutation (c.799C>T) in Labrador Retrievers, a missense mutation (c.848T>C) in Pugs, and a missense mutation (c.994G>A) in Beagles.

Clinical features: Affected dogs present as young adults with signs of severe macrocytic hypochromic regenerative hemolytic anemia, such as intermittent weakness. Moderate hepatosplenomegaly occurs by one year of age, followed by progressive osteosclerosis and myelofibrosis. Bone marrow and liver failure typically occur by 5 years of age. Carriers have no clinical signs, but have half-normal levels of erythrocyte pyruvate kinase activity (Giger et al., 1991). Bone marrow transplants have been used to alleviate clinical signs in affected dogs (Takatu et al., 2003).

Pathology: Red blood cells are dependent on ATP generated through glycolysis to maintain their Na/K pumps. Pyruvate kinase is a key enzyme in anaerobic glycolysis, converting phosphoenolpyruvate to pyruvate. Deficiency leads to inadequate ATP production, erythrocyte lysis or premature erythrocyte destruction by the spleen. Normal canine erythrocyte life span is approximately one month, whereas in affected dogs, the erythrocyte half-life is a few days (Giger et al., 1991). There are DNA tests available to detect the known causative mutations in basenjis and West Highland white terriers. Tests for erythrocyte pyruvate kinase activity are not accurate for diagnosis. There are other isoforms of pyruvate kinase in the dog that are encoded by different genes. The R-type is the only isoform expressed in normal canine erythrocytes. Affected dogs lack the R isoform, but enzyme activity in their erythrocytes typically appears elevated due to activity of the M2 isoform, (Whitney et al., 2005).

Control: Parents of affected dogs are obligate carriers. Siblings of affected dogs should be tested. Breeding of affected or carrier dogs is not recommended.

Genetic testing: There are tests available to detect the known causative mutations in the basenji and West Highland white terrier.

Breeds: Basenji, Beagle, Cairn Terrier, West Highland White Terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
PKLR pyruvate kinase, liver and RBC Canis lupus familiaris - no genomic information (-..-) PKLR Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Basenji Pyruvate kinase deficiency of erythrocyte PKLR deletion, small (<=20) a single base-pair deletion in exon 5 of the gene encoding R-type pyruvate kinase (PKLR) 1994 7520391
West Highland White terrier Pyruvate kinase deficiency of erythrocyte PKLR insertion, small (<=20) a 6 base pair insertion in exon 10 1999 10490091
Pug Pyruvate kinase deficiency of erythrocyte PKLR missense c.848T>C p.V283A 2012 22805166
Beagle Pyruvate kinase deficiency of erythrocyte PKLR missense c.994G>A p.G332S 2012 22805166
Labrador Retriever Pyruvate kinase deficiency of erythrocyte PKLR nonsense (stop-gain) g.42268632 c.799C>T p.Q267* 2012 22805166 20181218 Thanks to Maarten de Groot for advising FN of the genomic location

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2012 Gultekin, G.I., Raj, K., Foureman, P., Lehman, S., Manhart, K., Abdulmalik, O., Giger, U. :
Erythrocytic pyruvate kinase mutations causing hemolytic anemia, osteosclerosis, and seconday hemochromatosis in dogs. J Vet Intern Med 26:935-44, 2012. Pubmed reference: 22805166. DOI: 10.1111/j.1939-1676.2012.00958.x.
Trobridge, G.D., Beard, B.C., Wu, R.A., Ironside, C., Malik, P., Kiem, H.P. :
Stem cell selection in vivo using foamy vectors cures canine pyruvate kinase deficiency. PLoS One 7:e45173, 2012. Pubmed reference: 23028826. DOI: 10.1371/journal.pone.0045173.
2006 Harvey, J.W. :
Pathogenesis, laboratory diagnosis, and clinical implications of erythrocyte enzyme deficiencies in dogs, cats, and horses. Vet Clin Pathol 35:144-56, 2006. Pubmed reference: 16783707.
2003 Takatu, A., Nash, R.A., Zaucha, J.M., Little, M.T., Georges, G.E., Sale, G.E., Zellmer, E., Kuhr, C.S., Lothrop, C.D., Storb, R. :
Adoptive immunotherapy to increase the level of donor hematopoietic chimerism after nonmyeloablative marrow transplantation for severe canine hereditary hemolytic anemia. Biol Blood Marrow Transplant 9:674-82, 2003. Pubmed reference: 14652850. DOI: 10.1016/j.bbmt.2003.08.005.
1999 Kohn, B., Freistedt, R., Pekrun, A., Wang, P., Giger, U. :
Erythrocyte pyruvate kinase deficiency causing chronic hemolytic anemia and osteosclerosis in a longhaired dachshund [German] Kleintierpraxis 44:437-+, 1999.
Skelly, B.J., Wallace, M., Rajpurohit, Y.R., Wang, P., Giger, U. :
Identification of a 6 base pair insertion in West Highland White Terriers with erythrocyte pyruvate kinase deficiency American Journal of Veterinary Research 60:1169-1172, 1999. Pubmed reference: 10490091.
1995 Whitney, K.M., Lothrop, C.D. :
Genetic test for pyruvate kinase deficiency of basenjis Journal of the American Veterinary Medical Association 207:918-921, 1995. Pubmed reference: 7559024.
1994 Whitney, K.M., Goodman, S.A., Bailey, E.M., Lothrop, C.D. :
The molecular basis of canine pyruvate kinase deficiency Experimental Hematology 22:866-874, 1994. Pubmed reference: 7520391.
1992 Pekow, C.A., Hinds, T.R., Maggioprice, L., Hammond, W.P., Vincenzi, F.F. :
Osmotic Stress in Red Blood Cells from Beagles with Hemolytic Anemia American Journal of Veterinary Research 53:1457-1461, 1992. Pubmed reference: 1510326.
Schaer, M., Harvey, J.W., Calderwoodmays, M., Giger, U. :
Pyruvate Kinase Deficiency Causing Hemolytic Anemia with Secondary Hemochromatosis in a Cairn Terrier Journal of the American Animal Hospital Association 28:233-239, 1992.
1991 Giger, U., Noble, N.A. :
Determination of Erythrocyte Pyruvate Kinase Deficiency in Basenjis with Chronic Hemolytic Anemia Journal of the American Veterinary Medical Association 198:1755-1761, 1991. Pubmed reference: 2071475.
1990 Chapman, B.L., Giger, U. :
Inherited Erythrocyte Pyruvate Kinase Deficiency in the West Highland White Terrier Journal of Small Animal Practice 31:610-616, 1990.
1975 Prasse, K.W., Crouser, D., Beutler, E., Walker, M., Schall, W.D. :
Pyruvate kinase deficiency anemia with terminal myelofibrosis and osteosclerosis in a Beagle Journal of the American Veterinary Medical Association 166:1170-1175, 1975. Pubmed reference: 1141034.
1971 Searcy, G.P., Miller, D.R., Tasker, J.B. :
Congenital hemolytic anemia in the Basenji dog due to erythrocyte pyruvate kinase deficiency. Can J Comp Med 35:67-70, 1971. Pubmed reference: 4251418.
1969 Tasker, J.B., Severin, G.A., Young, S., Gillette, E.L. :
Familial anemia in the Basenji dog Journal of the American Veterinary Medical Association 154:158-165, 1969. Pubmed reference: 5812576.

Edit History


  • Created by Frank Nicholas on 12 Sep 2005
  • Changed by Martha MaloneyHuss on 23 Aug 2011
  • Changed by Frank Nicholas on 29 Aug 2011
  • Changed by Vicki Meyers-Wallen on 10 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 17 Aug 2012
  • Changed by Frank Nicholas on 31 Aug 2012
  • Changed by Frank Nicholas on 05 Jan 2013
  • Changed by Frank Nicholas on 28 Aug 2016