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.
