By examining the deleted regions in SMS patients with unusual-sized deletions, we refined the minimal SMS critical region (SMCR) to an approx 1.1-Mb genomic interval that contains 20 genes (16,26). The number, order, and orientation of genes within the SMCR are highly conserved in mouse chromosome 11, 32-34 cM (16). To identify the causative gene(s) in SMS, using chromosome engineering (35), we generated chromosomes carrying either the deletion/ deficiency (Df(11)17) or duplication (Dp(11)17) of an approx 2-Mb genomic interval containing the mouse region syntenic to the SMCR (36). These models partially reproduce the craniofacial and behavioral phenotype in humans (36,37). The Df(11)17/+ mice exhibit craniofacial abnormalities, seizures, marked obesity, abnormal circadian rhythm, and are hypoactive. The Dp(11)17/+ animals are underweight, hyperactive, and have impaired contextual fear conditioning. Most of the phenotypes in the Df(11)17/+ mice including craniofacial abnormalities, seizures, obesity, and some behavioral abnormities are rescued in Df(11)17/Dp(11)17 mice, suggesting the existence of a dosage-sensitive gene(s) in this approx 2-Mb genomic interval (37).
To refine regions responsible for different SMS phenotypic features, three lines of mice (Df17-1, Df17-2, and Df17-3) with approx 590-kb deletions were generated (38) using retrovirus mediated chromosome engineering for constructing nested deletions (39). Heterozygous mice with these smaller deletions manifest craniofacial anomalies and obesity (38). The identification of RAI1 point mutations in SMS patients suggest that haploinsufficiency of RAI1 causes the neurobehavioral, craniofacial, and otolaryngological phenotypes in SMS (20,21). Rai1, the mouse homolog of RAI1, is located in the smaller deletion. The heterozygous mice with disruption of Rai1 gene also exhibit a similar craniofacial phenotype and obesity (40), suggesting that Rai1 haploinsufficiency results in the craniofacial abnormalities and obesity in the smaller deletion mice.
Importantly, the severity and penetrance of the craniofacial phenotype were significantly reduced in the smaller deletion mice and Rai1+'~ heterozygous mice in comparison to Df(11)17/ + mice (38,40), indicating that genes or regulatory regions in the larger deletion that are not within the smaller deletion influence both the penetrance and expressivity of the phenotype. We observed phenotypic variation in these mouse models in both the same and different genetic backgrounds (38), perhaps reflecting the variations in SMS patients. Our studies on mouse models suggest that in SMS even a single clinical endophenotype such as craniofacial features is affected by multiple genes, in which RAI1 is the major causative gene, whereas other genes or regulatory regions within the SMCR, or located elsewhere, modify the phenotype. The molecular basis of dup(17)(p11.2p11.2) syndrome is still unknown. Examining whether the Rai1 mutant allele can rescue the phenotype in Dp(11)17/+ mice will help understand the role of RAI1 in this disorder.
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