Generation of a mouse model for Familial Dysautonomia.

描述(由申请人提供)：家族性自主神经障碍(FD)是一种常染色体隐性遗传病，影响德系犹太人人口中1/3,600名活产婴儿。这种衰弱的疾病的特征是感觉和自主神经系统发育不良、存活和进行性退化。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，主要的单倍型(-gt；98%的FD病例)与Ikbkap基因(编码IKAP蛋白)内含子20的供体剪接点第6位的T？C转变有关。这种突变导致了外显子20被剪接掉的mRNA的产生，导致了框架移位，并产生了79kD的截断蛋白。IKAP的正常功能以及导致FD神经系统进行性退行性变的机制尚不清楚。在我们提出的研究中，我们将1)分析Ikbkap在小鼠中的表达模式，以确定IKAP可能在其中发挥关键作用的组织；2)使用两种策略建立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，这在原则上应该导致产生截断的蛋白质。然而，这两个物种之间在剪接识别方面的潜在差异可能会干扰使用这种方法生成FD模型。作为另一种策略，我们建议产生外显子20的缺失。这两个小鼠品系将并行产生。这些小鼠的初步特征将包括行为、生理和组织病理学分析。如果成功地产生了小鼠模型，它将可供科学界进一步鉴定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.