In other species: domestic cat

Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 266200 (trait) , 609712 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009950: pyruvate kinase deficiency of red cells

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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).

Breeds: Basenji (Dog) (VBO_0200120), Beagle (Dog) (VBO_0200131), Cairn Terrier (Dog) (VBO_0200267), Chihuahua (Dog) (VBO_0200338), Dachshund (Dog) (VBO_0200406), Labrador Retriever (Dog) (VBO_0200800), Poodle, Miniature (Dog) (VBO_0201051), Pug (Dog) (VBO_0201089), Toy American Eskimo Dog (Dog) (VBO_0201358), West Highland White Terrier (Dog) (VBO_0201415).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: