Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome associated with an interstitial deletion of chromosome 17p11.2. Phenotypic characteristics include mental retardation, self- injurious behavior, myopia, hearing loss, delayed physical and motor development, craniofacial and skeletal anomalies, and sleep disturbances. The deletions observed in patients can range from less than 2 to greater than 9 megabases of DNA and may include more than 100 genes. The average size of the common deletion on chromosome 17 is estimated to be 4-5 Mb, while the critical interval for chromosome involvement is approximately 1.5-2 Mb. Even though the molecular basis of Smith-Magenis syndrome is unknown, 17p11.2 has been found to be an extremely gene-rich region. We have mapped several genes within the SMS region, although none of these genes have truly been implicated in the SMS phenotype. Since it is likely the SMS phenotype is caused by haploinsufficiency for several genes, it is critical to identify all genes and assess the potential role of each of these genes within the critical deletion interval. The ultimate goals of this project are to identify sequence, and characterize genes within the critical interval toward understanding their potential role in the SMS phenotype. In order to achieve these goals, a transcriptional map will be generated. Expressed sequences are being obtained from this interval through a variety of standard positional cloning techniques, including contig generation, direct sequencing, and cDNA library screening. All identified genes will be analyzed, their expression patterns determined, and possible functions elucidated in an attempt to identify potentially dosage-sensitive genes from among the many genes we may find within this deletion interval. Genes may be discovered that are involved in neurological development, behavior, skeletal and craniofacial development, and sleep/circadian rhythm. Importantly, these genes may have greater implication in other disease entities that exhibit partial phenotypes with similarity to SMS. Detailed analysis will initially focus on one gene within the critical interval called developmentally regulated GTP-binding protein 2 (DRG2). We have cloned the Drosophila DRG2 homolog, and studies are currently underway towards it characterization in fly embryos. The molecular dissection of a microdeletion syndrome required detailed analysis of all genes within the critical region towards determining the potential effect of haploinsufficiency and the role these genes may play in the generation of the phenotype. The work proposed here will lay the foundation on which the gene(s) responsible for SMS and other developmental process may be elucidated.
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