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Human Molecular Genetics Advance Access originally published online on September 30, 2004
Human Molecular Genetics 2004 13(21):2613-2624; doi:10.1093/hmg/ddh288
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Human Molecular Genetics, Vol. 13, No. 21 © Oxford University Press 2004; all rights reserved

Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith–Magenis syndrome

Jiong Yan1, Victoria W. Keener1, Weimin Bi1, Katherina Walz1, Allan Bradley4, Monica J. Justice1 and James R. Lupski1,2,3,*

1Department of Molecular and Human Genetics and 2Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA, 3Texas Children's Hospital, Houston, TX, USA and 4The Wellcome Trust Sanger Institute, Hinxton, UK

Received May 25, 2004; Revised September 4, 2004; Accepted September 10, 2004

Smith–Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with del(17)(p11.2p11.2). The phenotype is variable even in patients with deletions of the same size. RAI1 has been recently suggested as a major gene for majority of the SMS phenotypes, but its role in the full spectrum of the phenotype remains unclear. Df(11)17/+ mice contain a heterozygous deletion in the mouse region syntenic to the SMS common deletion, and exhibit craniofacial abnormalities, seizures and marked obesity, partially reproducing the SMS phenotype. To further study the genetic basis for the phenotype, we constructed three lines of mice with smaller deletions [Df(11)17-1, Df(11)17-2 and Df(11)17-3] using retrovirus-mediated chromosome engineering to create nested deletions. Both craniofacial abnormalities and obesity have been observed, but the penetrance of the craniofacial phenotype was markedly reduced when compared with Df(11)17/+ mice. Overt seizures were not observed. Phenotypic variation has been observed in mice with the same deletion size in the same and in different genetic backgrounds, which may reflect the variation documented in the patients. These results indicate that the smaller deletions contain the gene(s), most likely Rai1, causing craniofacial abnormalities and obesity. However, genes or regulatory elements in the larger deletion, which are not located in the smaller deletions, as well as genes located elsewhere, also influence penetrance and expressivity of the phenotype. Our mouse models refined the genomic region important for a portion of the SMS phenotype and provided a basis for further molecular analysis of genes associated with SMS.

* To whom correspondence should be addressed at: Department of Molecular and Human Genetics, Baylor College of Medicine, Room 604B, One Baylor Plaza, Houston, TX 77030, USA. Tel: +1 7137986530; Fax: +1 7137985073; Email: jlupski{at}bcm.tmc.edu


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