Exploring the Reversibilty of the Smith-Magenis Syndrome Phenotype

描述（由申请人提供）：基因组疾病是常见疾病（约1/1000出生），通常是由从头重排引起的散发性疾病（3）。临床表型是位于重排的基因组片段内的基因的异常剂量的结果。SMS是一种具有与染色体17p11.2中3.7 Mb微缺失相关的多个先天性异常的基因组病症。通过染色体工程，我们已经产生了SMS的小鼠模型Df（II）17/+，其概括了在人类患者中观察到的表型（21，22）。最近，视黄酸诱导1基因（RAI 1）的突变已被确定为SMS的病因（11）。此外，Rail无效的小鼠表现出SMS相关的异常（22）。该项目假设，在适当的时间恢复Rail蛋白的正常基因剂量可能会阻止SMS小鼠模型中观察到的至少一些表型的发展。这一假说涉及两个关键问题：疾病表型是否可逆？如果是这样，什么时候开始开始治疗太晚了？为了回答这些问题，我们建议：1。产生小鼠，其中我们可以控制铁路的时空表达。我们将产生在SMS的同线关键区域中具有杂合缺失和可诱导的野生型Rail等位基因的小鼠。为此，我们建议产生2个转基因小鼠：1个在四环素应答启动子下游携带野生型Rail的额外拷贝，第二个1携带在Rail特异性启动子控制下表达四环素应答转录因子（tTA）的修饰的BAG转基因。通过这种方式，Rail转基因的表达可以在疾病进展的不同阶段以Rail启动子依赖性方式启动。2.表征在不同时间点以适当剂量恢复Rail的表型效应。我们将进行表型分析，观察颅面发育、体重和癫痫发作，作为表型可逆性或可预防性的第一和快速指标。此外，将使用行为测试来评估运动活动和昼夜节律。本提案的目的是研究当在SMS小鼠模型中以适当的时空方式校正Rail基因剂量时，Smith-Magenis Syndorme（SMS）的可逆性。这项研究将主要在智利科学研究中心（CECS）与Katherina Walz博士合作进行，作为NIH资助#RO 1 DEI 5210 -02的延伸。

DESCRIPTION (provided by applicant): Genomic disorders are frequent diseases (~1 per 1000 births) and often sporadic resulting from de novo rearrangements (3). The clinical phenotype is a consequence of abnormal dosage of a gene(s) located within the rearranged genomic fragment(s). SMS is a genomic disorder with multiple congenital anomalies associated with a microdeletion of 3.7 Mb in chromosome 17pl 1.2. By chromosome engineering we have generated a mouse model for SMS, Df(ll)17/+, that recapitulates phenotypes observed in human patients (21, 22). Recently, mutations in the retinoic acid induced 1 gene (RAI1) have been identified as causative of SMS (11). Additionally, mice null for Rail exhibit SMS-related abnormalities (22). This project postulates that restoring the normal gene dosage of Rail protein at an appropriate time might prevent the development of at least some of the phenotypes seen in the mouse model for SMS. This hypothesis entails 2 critical questions: Is the disease phenotype reversible? If so, when is it too late to begin therapy? To answer these questions, we propose to: 1. Generate mice in which we can control the spatial-temporal expression of Rail. We will produce mice that harbor a heterozygous deletion in the syntenic critical region of SMS and an inducible wild-type Rail allele. For this we propose to generate 2 transgenic mice: 1 that harbors an extra copy of wild-type Rail downstream of a tetracycline-responsive promoter, and a second 1 carrying a modified BAG transgene expressing the tetracycline-inhibitable transcription factor (tTA) under the control of Rail specific promoter. In this way, expression of the Rail transgene can be initiated in a Rail promoter-dependent manner at different stages of disease progression. 2. Characterize the phenotypic effects of restoring Rail at a proper dosage at various time points. We will perform phenotypic analysis, observing craniofacial development, body weight, and seizures as a first and quick indication of reversibility or preventability of the phenotype. In addition, behavioral tests will be used to evaluate locomotor activity, and circadian rhythm. The goal of this proposal is to study the reversibility of Smith-Magenis Syndorme (SMS) when the Rail gene dosage is corrected at an appropriate spacio-temporal manner in a mouse model for SMS. This research will be done primarily in Chile at the Centre de Estudios Cientificos (CECS), in collaboration with Dr. Katherina Walz, as an extention of NIH grant #RO 1 DEI5210-02.