Generation of a mouse model for Familial Dysautonomia.

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DESCRIPTION (provided by applicant): Familial Dysautonomia (FD) is an autosomal recessive disorder that affects 1/3,600 live births in the Ashkenazi Jewish population. This debilitating disorder is characterized by poor development, survival and progressive degeneration of the sensory and autonomic nervous system. Despite recent advances, the disorder is inevitably fatal, with only 50% of patients reaching the age 30. In FD the major haplotype (>98% of the FD cases), is associated with a T?C transition in position 6 of the donor splice site of intron 20 of the Ikbkap gene (which encodes the IKAP protein). This mutation results in the generation of an mRNA in which exon 20 is spliced out causing a frameshift and producing a truncated protein of 79kD. The normal function of IKAP as well as the mechanisms leading to the progressive degeneration of the nervous system in FD remain unknown. In our proposed studies we will 1) analyze the pattern of expression of Ikbkap in the mouse to identify the tissues where IKAP may play an essential role and 2) generate a mouse model for FD using two strategies: The first strategy consists in replicating the human point mutation in intron 20 of the mouse gene, which should in principle lead to the production of a truncated protein. Potential differences in splicing recognition between the two species may however interfere with the generation of an FD model using this approach. As an alternative strategy, we propose to generate a deletion of exon 20. These two mouse lines will be generated in parallel. A preliminary characterization of these mice will include behavioral, physiological and histopathological analyses. If a successful mouse model is generated it will be made available for the scientific community for further characterization and for testing potential therapeutic strategies.