Facial dysmorphology is a consistent feature of many malformation syndromes. Recognition of dysmorphic patterns and specific facial features can be essential for establishing a diagnosis in such genetic conditions. However, the molecular basis for facial dysmorphology remains largely unknown. Distinct craniofacial features have been described for Smith-Magenis syndrome (SMS), a microdeletion syndrome associated with an ~4 Mb interstitial deletion of the short arm of chromosome 17 in band p11.2. In addition to craniofacial abnormalities, the clinical features include mental retardation, behavioral problems, and sleep disturbance. We have refined the critical region (SMCR) responsible for the SMS phenotype to an approximately 1.1 Mb interval that is highly conserved between humans and mice. By chromosome engineering we have generated Df(17) mice encompassing a genetic deletion corresponding to the syntenic region of the human SMS deleted interval. Craniofacial abnormalities have been observed in those mice. Thus, the gene(s) responsible for craniofacial anomalies in SMS has been narrowed to a relatively small (approximately 1Mb), well defined, complete and annotated genomic sequence for both human and the mouse genomic region. This proposal seeks to identify the genes that cause craniofacial defects in SMS. The mechanisms for craniofacial defects will be studied further by a combination of skeletal and histological analysis. We propose to rescue the phenotype in the Df(17) mice using mouse genomic clones from the interval syntenic to the human SMCR. The expression profiles of genes within these genomic clones will be examined and the candidate genes will be mutated in mice by gene targeting with the hypothesis that homozygous null alleles will likely have a more profound effect on craniofacial development than those resulting from haploinsuffciency. Studies in this proposal will determine the causative genes responsible for the facial features of SMS. Many of these features are also observed in other mental retardation syndromes. Furthermore, our investigations will likely aid in the understanding of the genetic regulation of normal craniofacial development as well as the development of anomalies associated with SMS.
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