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Molecular and Cellular Biology, May 2003, p. 3646-3655, Vol. 23, No. 10
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.10.3646-3655.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) Contiguous Gene Syndromes by Chromosome Engineering in Mice: Phenotypic Consequences of Gene Dosage Imbalance

Departments of Molecular and Human Genetics,¹ Pediatrics,⁵ Neurology (Neurosensory Center), Baylor College of Medicine,² Texas Children's Hospital, Houston, Texas,⁶ Department of Pathology (Neuropathology), Stanford University Medical Center, Stanford, California,³ Sanger Centre, Cambridge, United Kingdom⁴

Received 3 January 2003/ Returned for modification 11 February 2003/ Accepted 27 February 2003

Contiguous gene syndromes (CGS) are a group of disorders associated with chromosomal rearrangements of which the phenotype is thought to result from altered copy numbers of physically linked dosage-sensitive genes. Smith-Magenis syndrome (SMS) is a CGS associated with a deletion within band p11.2 of chromosome 17. Recently, patients harboring the predicted reciprocal duplication product [dup(17)(p11.2p11.2)] have been described as having a relatively mild phenotype. By chromosomal engineering, we created rearranged chromosomes carrying the deletion [Df(11)17] or duplication [Dp(11)17] of the syntenic region on mouse chromosome 11 that spans the genomic interval commonly deleted in SMS patients. Df(11)17/+ mice exhibit craniofacial abnormalities, seizures, marked obesity, and male-specific reduced fertility. Dp(11)17/+ animals are underweight and do not have seizures, craniofacial abnormalities, or reduced fertility. Examination of Df(11)17/Dp(11)17 animals suggests that most of the observed phenotypes result from gene dosage effects. Our murine models represent a powerful tool to analyze the consequences of gene dosage imbalance in this genomic interval and to investigate the molecular genetic bases of both SMS and dup(17)(p11.2p11.2).

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