Smith-Magenis syndrome (SMS) is a multiple congenital anomaly mental retardation syndrome associated with a heterozygous deletion of human chromosome 17 band p11.2 [del(p11.2)]. This micro-deletion syndrome has an estimated prevalence of at least 1 in 20-25,000 live births, making it one of the most frequently observed chromosomal deletions in humans. Clinical features include mental retardation, short stature, minor craniofacial anomalies, short fingers, microcornea, developmental defects of the heart and kidneys, and neurobehavioral abnormalities such as self destructive, aggressive behavior, seizures and absent rapid eye movement (REM) sleep. The complex phenotypic features suggest deletion of several contiguous genes, and the phenotypic effects are hypothesized to result from haploinsufficiency. Although seventeen genes have been identified in the SMS common deletion region, their contribution to this complex phenotype remains speculative. Chromosome 17p11.2 is syntenic to the 32-34 cM region of mouse chromosome 11. Few genes have been mapped to both the mouse and human regions of synteny including: Aldh3 encoding aldehyde dehydrogenase 3, the Llgl gene encoding the Drosophila homologue for the lethal 92) giant larvae gene, Serk1 encoding a protein kinase activator of the SAPK signal transduction cascade, and the Pmp22 gene encoding the 22 KD peripheral myelin protein; all three of which map at 33 cM. Other genes in 17p11.2 likely have murine homologues as well. This proposal seeks to characterize the genomic region of murine syteny to 17p11.2p12 and analyze the consequence of haploinsufficiency of the mouse loci by construction of knockouts of the genes involved. As part of the program project grant we seek to use chromosome engineering to construct different deletions of mouse chromosome 11 containing the syntenic regions for portions of the human SMS deletion interval. Extensive characterization of the engineered mice will then be performed to determine the consequences of gene haploinsufficiency. These analyses will contributes to the understanding of the molecular basis of the SMS chromosomal micro-deletion syndrome and will have potent implications for human development and biology.
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