Enu Mutagenesis Identifies a Novel Platelet Phenotype in a Loss-Of-Function Jak2 Allele

Utilizing ENU mutagenesis, we identified a mutant mouse with elevated platelets. Genetic mapping localized the mutation to an interval on chromosome 19 that encodes the Jak2 tyrosine kinase. We identified a A3056T mutation resulting in a premature stop codon within exon 19 of Jak2 (Jak2^K915X), resulting in a protein truncation and functionally inactive enzyme. This novel platelet phenotype was also observed in mice bearing a hemizygous targeted disruption of the Jak2 locus (Jak2^+/-). Timed pregnancy experiments revealed that Jak2^K915X/K915X and Jak2^-/- displayed embryonic lethality; however, Jak2^K915X/K915X embryos were viable an additional two days compared to Jak2^-/- embryos. Our data suggest that perturbing JAK2 activation may have unexpected consequences in elevation of platelet number and correspondingly, important implications for treatment of hematological disorders with constitutive Jak2 activity.