Towards a Mouse Model of Thrombocytopenia with Absent Radius (TAR) Syndrome. V. L. Horner1, A. Dodd1, A. Long1, C. L. Martin2, T. Caspary1 1) Human Genetics, Emory University School of Medicine, Atlanta, GA; 2) Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA.
TAR syndrome is characterized by low blood platelet counts (thrombocytopenia) and absence of the radius bone in each forearm. Thrombocytopenia can lead to easy bruising and/or hemorrhage in infancy, which may become less severe over time. The absence of radius bones results in shortened forearms. TAR syndrome is inherited in an autosomal recessive manner and is due to changes in the gene RBM8A. Compound inheritance of one RBM8A null allele (most often as a large deletion) and one RBM8A hypomorphic allele causes TAR syndrome. At present, two hypomorphic alleles have been described. Somewhat surprisingly, both alleles contain the minor allele of a single nucleotide polymorphism (SNP) in a regulatory region of RBM8A. These two regulatory SNPs lower RBM8A transcription in vitro. Further, the level of the RBM8A gene product, Y14, is reduced in individuals who carry the SNPs compared to wild-type controls. Together, these results lead to the hypothesis that there is a dose-effect phenomenon, in which a null allele together with a hypomorphic allele brings Y14 levels below some critical threshold to cause TAR syndrome. To determine where, when and how much RBM8A production is required during embryonic development, we are generating mouse alleles in which the endogenous RBM8A locus is under the control of a tetracycline-dependant transactivator. This system will enable us to control the amount of Y14 protein available during embryogenesis, by varying the amount of tetracycline fed to pregnant mothers. We are generating two strains of mice: the first strain will have the transactivator (TetOn) under the control of the endogenous RBM8A promoter. The second strain will have the tetracycline-responsive promoter (tetO) driving RBM8A expression. The presence of tetracycline allows the transactivator to bind and drive RBM8A transcription. There is a linear relationship between the amount of tetracycline and the amount of transcription, enabling us to define the critical dosage threshold of Y14 that causes TAR syndrome phenotypes as well as the dosage that causes lethality. Ultimately, this system will also allow us to examine the temporal and spatial requirements for RBM8A during development, by providing tetracycline to pregnant mothers at various stages of embryogenesis and by driving the transactivator with promoters specific for various tissues. These experiments are the first step to defining the therapeutic level of Y14 for TAR syndrome treatment.
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