Generation of a mouse model for Familial Dysautonomia.

描述（由申请人提供）：家族性自主神经功能障碍（FD）是一种常染色体隐性遗传疾病，影响德系犹太人人口中1/3，600的活产婴儿。这种使人衰弱的疾病的特征是感觉和自主神经系统的发育、存活和进行性退化不良。尽管最近取得了进展，但这种疾病不可避免地是致命的，只有50%的患者达到30岁。在FD中，主要单倍型（>98%的FD病例）与T？Ikbkap基因（编码IKAP蛋白）内含子20供体剪接位点6位的C转换。该突变导致产生mRNA，其中外显子20被剪接掉，引起移码并产生79 kD的截短蛋白。IKAP的正常功能以及导致FD神经系统进行性变性的机制尚不清楚。在我们提出的研究中，我们将1）分析小鼠中Ikbkap的表达模式，以确定IKAP可能发挥重要作用的组织，2）使用两种策略生成FD的小鼠模型：第一种策略包括复制小鼠基因内含子20中的人类点突变，原则上应导致产生截短蛋白。然而，两个物种之间的剪接识别的潜在差异可能会干扰使用这种方法的FD模型的生成。作为替代策略，我们建议产生外显子20的缺失。这两条鼠标线将并行生成。这些小鼠的初步表征将包括行为、生理和组织病理学分析。如果成功地生成了小鼠模型，它将可供科学界进一步表征和测试潜在的治疗策略。

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.