PYRUVATE KINASE DEFICIENCY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Erythrocyte pyruvate kinase (PK) deficiency is the most common glycolytic erythroenzymopathy in humans and resulats in a moderate to severe hemolytic anemia. Similarly, dogs with PK deficiency have severe hemolytic anemia, but they also develop a myelofibrosis and osteosclerosis. After the original discovery of the first mutation in PK-deficient beagles we have now identified disease causing mutations in West Highland white and Cairn terriers, Beagles, Eskimo toy, and dachshund. We also identified PK-deficiency in Abyssinian, Somali, and domestic shorthaired cats. These cats experienced an intermittent hemolytic anemia. Their erythrocytes have less than 10% PK activity and there is no anomalous expression of M-PK. Molecular genetic analysis revealed a 13bp deletion in exon 6 due to a single base pair mutation in intron 6 that results in alternate splicing and truncation of the protein. A small number of cats are being kept for collaborative gene transfer studies with Clint Lothrop, DVM, PhD at Auburn University. Despite the identification of the various mutations the full-length cDNA has not been reported. This is of particular interest as there is different splicing responsible for the R and L isoforms and the further structure may explain the anomalous expression of M-type PK in dogs, which seems to be dysfunctional in red blood cells. Based upon the recent completion of the canine genome sequence and partial information on the feline genome sequence, we should be able to complete these studies which will also permit the generation of species-specific full length cDNAs for gene transfer studies.