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

Anderson, Nicole; Javadi, Mojib; Berndl, Elizabeth; Berberovic, Zorana; Bailey, Monica L.; Huang, Kai; Flenniken, Ann M.; Osborne, Lucy R.; Adamson, S. Lee; Rossant, Janet; Carter‐Su, Christin; Wang, Chen; McNagny, Kelly M.; Paulson, Robert F.; Minden, Mark D.; Stanford, William L.; Barber, Dwayne L.

doi:10.1371/journal.pone.0075472

PLoS ONE

2013

DOI: 10.1371/journal.pone.0075472

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

Nicole Anderson

Mojib Javadi

Elizabeth Berndl

et al.

Abstract: 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 experime… Show more

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“…In addition to this genetic recombination toolkit, several chemical mutagenesis programs based on the treatment of gametes with N-nitroso-N-ethylurea followed by systematic phenotypic screening have been established to increase the frequency of mutations potentially targeting the hematopoietic system. [4][5][6] This approach might allow one to direct the screening of novel genes in patients with unidentified congenital thrombocytopenias.…”

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The contribution of mouse models to the understanding of constitutional thrombocytopenia

et al. 2016

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Article summary• Constitutional thrombocytopenias of hereditary origin have long been poorly studied due to the difficulties of obtaining invasive marrow samples.• Genetic engineering has allowed the generation of numerous mouse models for all these pathologies, providing invaluable information to understanding these diseases and serving as preclinical models to test new therapies.Constitutional thrombocytopenias result from genetic mutations affecting platelet production. These rare diseases are still underdiagnosed, especially in adults, because they remain little-known and have a highly variable expression. Autoimmune thrombocytopenia is still often wrongly diagnosed, thereby leading to the inadequate management of patients, with occasionally inappropriate splenectomy. The diagnosis of congenital thrombocytopenia relies on cytological and functional platelet analyses performed almost exclusively in specialized laboratories. Furthermore, about 50% of thrombocytopenias, associated or not with a thrombopathy, still remain of unknown origin. 1 In cases where platelet studies orient the diagnosis to a known disease, the detection of mutations in the suspected genes can C onstitutional thrombocytopenias result from platelet production abnormalities of hereditary origin. Long misdiagnosed and poorly studied, knowledge about these rare diseases has increased considerably over the last twenty years due to improved technology for the identification of mutations, as well as an improvement in obtaining megakaryocyte culture from patient hematopoietic stem cells. Simultaneously, the manipulation of mouse genes (transgenesis, total or conditional inactivation, introduction of point mutations, random chemical mutagenesis) have helped to generate disease models that have contributed greatly to deciphering patient clinical and laboratory features. Most of the thrombocytopenias for which the mutated genes have been identified now have a murine model counterpart. This review focuses on the contribution that these mouse models have brought to the understanding of hereditary thrombocytopenias with respect to what was known in humans. Animal models have either i) provided novel information on the molecular and cellular pathways that were missing from the patient studies; ii) improved our understanding of the mechanisms of thrombocytopoiesis; iii) been instrumental in structure-function studies of the mutated gene products; and iv) been an invaluable tool as preclinical models to test new drugs or develop gene therapies. At present, the genetic determinants of thrombocytopenia remain unknown in almost half of all cases. Currently available high-speed sequencing techniques will identify new candidate genes, which will in turn allow the generation of murine models to confirm and further study the abnormal phenotype. In a complementary manner, programs of random mutagenesis in mice should also identify new candidate genes involved in thrombocytopenia.The contribution of mouse models to the understanding of constitutional thrombocytope...

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The contribution of mouse models to the understanding of constitutional thrombocytopenia

et al. 2016

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A novel JAK2 R564* variant in a patient with thrombocytosis

Villanueva

Poon

Gallardo

et al. 2019

Int J Lab Hematology

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

Cited by 2 publications

References 55 publications

The contribution of mouse models to the understanding of constitutional thrombocytopenia

The contribution of mouse models to the understanding of constitutional thrombocytopenia

A novel JAK2 R564* variant in a patient with thrombocytosis

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