The Smith-Magenis (SMS) is a microdeletion syndrome associated with a proximal deletion of the short arm of chromosome 17 in band p11.2 The spectrum of clinical findings includes mental retardation, short status, dysmorphic features, multiple congenital anomalies, sleep disturbances and behavioral problems. We previously demonstrated that homologous recombination of a large (>200 kb) flanking repeat sequence, which consist of a repeat gene cluster (SMS-REP) including at least four genes of pseudogenes (CLP, KER, SRP, and TRE), is responsible for the del(17)(p11.2p11.2) associated with SMS. Homologous recombination using flanking repeat gene cluster as substrates has recently been shown to be the molecular mechanism for several other microdeletion syndromes. This project will investigate the mechanism for an interstitial microdeletion syndrome using SMS as a model. The DNA rearrangements breakpoints will be investigated from patients with the rearrangement and comparable genomic regions will be studied from normal controls and non-human primates. We propose to determine the DNA sequences of SMS-REP and construct a long range restriction map of the 5 Mb SMS common deletion region. This information will be utilized to examine the products of recombination in multiple SMS patients with the common deletion and to map breakpoints of patients with chromosome rearrangements involving 17p11.2. Patients with duplication of 17p11.2 will be investigated to determine if the duplication DNA rearrangement represents the reciprocal recombination product of the SMS common deletion. Our studies will provide information to determine the mechanistic basis of interstitial deletions and duplications. These chromosome rearrangements represent a relatively common cause of mental retardation. Furthermore, our investigations may help uncover common features of rearrangement prone regions of the human genome and will likely lead to development of new diagnostic test for identifying interstitial deletions and duplications.
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