OMIA:000844-9615 : Pyruvate kinase deficiency of erythrocyte in Canis lupus familiaris
In other species: domestic cat
Categories: Homeostasis / metabolism phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 266200 (trait) , 609712 (gene)
Links to MONDO diseases:
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.
|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|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|897||Basenji||Pyruvate kinase deficiency of erythrocyte||PKLR||deletion, small (<=20)||Naturally occurring variant||CanFam3.1||7||g.42267825del||c.433del||p.(P145Rfs*23)||NM_001256262.1; NP_001243191.1||1994||7520391|
|896||Labrador Retriever||Pyruvate kinase deficiency of erythrocyte||PKLR||nonsense (stop-gain)||Naturally occurring variant||CanFam3.1||7||g.42268632C>T||c.799C>T||p.(Q267*)||NM_001256262.1; NP_001243191.1||2012||22805166||20181218 Thanks to Maarten de Groot for advising FN of the genomic location|
|894||Pug||Pyruvate kinase deficiency of erythrocyte||PKLR||missense||Naturally occurring variant||CanFam3.1||7||g.42268681T>C||c.848T>C||p.(V283A)||NM_001256262.1; NP_001243191.1||2012||22805166|
|895||Beagle||Pyruvate kinase deficiency of erythrocyte||PKLR||missense||Naturally occurring variant||CanFam3.1||7||g.42268927G>A||c.994G>A||p.(G332S)||NM_001256262.1; NP_001243191.1||2012||22805166|
|898||West Highland White Terrier||Pyruvate kinase deficiency of erythrocyte||PKLR||insertion, small (<=20)||Naturally occurring variant||CanFam3.1||7||g.42269752_42269757dup||c.1333_1338dup||p.(K445_T446dup)||NM_001256018.1; NP_001242947.1; the original publication described "a 6 base pair insertion in exon 10". In accordance with HGVS recommendations, the variant is annotated in this table as a 6 bp duplication and updated a recent reference sequences. This shifts the position of the predicted amino acid change by about 21 amino acids.||1999||10490091|
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 .|
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