Exploring the Reversibilty of the Smith-Magenis Syndrome Phenotype

基因组疾病是常见疾病（约每1000名新生儿中有1例），通常是新发疾病引起的散发性疾病。 重排（3）。临床表型是位于细胞内的基因的异常剂量的结果。 重排的基因组片段。SMS是一种具有多种先天性异常的基因组疾病 与染色体17 p11.2中3.7 Mb的微缺失相关。通过染色体工程， 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）突变已被确定为SMS的病因 （十一）、此外，Rail无效的小鼠表现出SMS相关的异常（22）。该项目假设， 在适当的时候恢复Rail蛋白的正常基因剂量可能会阻止at 至少在SMS小鼠模型中观察到的一些表型。这一假设涉及两个关键问题： 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：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缺失的小鼠。 野生型Rail等位基因。为此，我们建议产生两只转基因小鼠：一只携带额外的 野生型Rail位于四环素应答启动子下游，第二个携带修饰的BAG 在Rail特异性调控下表达四环素可降解转录因子（tTA）的转基因 启动子以这种方式，Rail转基因的表达可以以Rail启动子依赖性方式启动 在疾病发展的不同阶段。2.表征在适当的温度下恢复Rail的表型效应， 剂量在不同的时间点。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示。在 此外，行为测试将用于评估自发活动和昼夜节律。 本提案的目的是研究Smith-Magenis Syndorme（SMS）的可逆性， 在SMS的小鼠模型中以适当的时空方式校正剂量。 这项研究将主要在智利科学研究中心（CECS）进行， 与Katherina Walz博士合作，作为NHI资助#RO 1DEI 5210 -02的延伸。

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 two 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 two transgenic mice: one that harbors an extra copy of wild-type Rail downstream of a tetracycline-responsive promoter, and a second one 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 reversibilityor 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 NHI grant #RO 1DEI5210-02.