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European Journal of Human Genetics (2008) 16, 941954 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00
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How much is too much? Phenotypic consequences of Rai1 overexpression in mice
Santhosh Girirajan1, Nisha Patel2,3, Rebecca E Slager4, Mary E Tokarz5, Maja Bucan6, Jenny L Wiley5 and Sarah H Elsea*,1,2
1Department of Human Genetics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA; 2Department of Pediatrics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA; 3Faculty of Health and Life Sciences, University of the West of England, Bristol, UK; 4Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 5Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA;
6Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA The retinoic acid induced 1 (RAI1) gene when deleted or mutated results in SmithMagenis syndrome (SMS), while duplication of 17p11.2, including RAI1, results in the dup(17)(p11.2) syndrome characterized by mental retardation, growth and developmental delays, and hyperactivity. Mouse models for these human syndromes may help define critical roles for RAI1 in mammalian development and homeostasis that otherwise cannot be deduced from patient studies. A mouse model for duplication, Dp(11)17 , involving Rai1 has been reported. However, this mutant was engineered on a mixed genetic background confounding phenotypic effects due to possible modifier genes. We have therefore created and evaluated mice with a graded series of four (hemizygous) and six (homozygous) copies of Rai1, and overexpressing Rai1 41.5-fold and 42-fold, respectively. Data show that Rai1-transgenic mice have growth retardation, increased locomotor activity, and abnormal anxiety-related behavior compared to wild-type littermates. Rai1-transgenic mice also have an altered gait with short strides and long sways, impaired ability on a cage-top hang test, decreased forelimb grip strength, and a dominant social behavior. Further, analyses of homozygous transgenic mice revealed a dosage-dependent exacerbation of the phenotype, including extreme growth retardation, severe neurological deficits, and increased hyperactivity. Our results show that Rai1 dosage has major consequences on molecular processes involved in growth, development, and neurological and behavioral functions, thus providing evidence for several dosage-thresholds for phenotypic manifestations causing dup(17)(p11.2) syndrome or SMS in humans. European Journal of Human Genetics (2008) 16, 941954; doi:http://dx.doi.org/10.1038/ejhg.2008.21
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