Del(17)(p11.2) or Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome which is associated with an interstitial deletion of band p11.2 of the short arm of chromosome 17. The consistent clinical features of SMS patients include dysmorphic features, short stature, and developmental delay. Variable clinical features include cleft lip/palate, congenital heart defects, microcornea, sleep disturbances including absent REM sleep, signs of peripheral neuropathy, aggressive and self-destructive behavior. We have identified over 40 unrelated patients demonstrating del(17)(p11.2) by high resolution cytogenetics and established lymphoblastoid cell lines on these patients. DNA and cell lines are also available on one or both parents of the majority of these patients. The long term objective of this study is to understand the molecular basis of SMS. This application proposes to determine the approximate size of the deletion in key patients by dual beam laser flow cytometry. The parental origin and molecular extent of the deletions will be determined by Southern analysis with markers mapping to the deletion interval. A panel of somatic cell hybrids which include the affected chromosome 17 from key SMS deletion or translocation patients will be constructed. Overlapping yeast artificial chromosome clones and cosmids encompassing the deletion interval will be isolated and contigs established. Additional markers if essential will be created by Alu- and LINE-PCR of radiation hybrids retaining 17p11.2 sequences and by microdissection cloning of 17p11.2. A long range physical map of the region encompassing the deletion interval in the human genome will be constructed. The deletion breakpoints in SMS patients will be identified, cloned and the sequence determined. A genetic map of the syntonic regions in the mouse genome will be obtained using conserved sequences identified from these clones. Expressed sequences will be sought and appropriate cDNA libraries will be screened to identify candidate genes responsible for behavioral and REM sleep abnormalities, ocular, cardiac and craniofacial abnormalities and for neuropathy. The correlated physical and phenotype map of 17p11.2 and the identification of candidate genes will in the long term provide valuable information on the basis of these latter disorders and provide valuable reagents for the diagnosis, treatment and possibly correction of this syndrome.
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