Abstract
The retinoic acid induced 1 (RAI1) gene when deleted or mutated results in Smith–Magenis 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 >1.5-fold and >2-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.
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Acknowledgements
We acknowledge Dr Mario Dance at Virginia Commonwealth University for helping with collection of blood samples and care of mice, Dr Thom Saunders and Elizabeth Hughes from the University of Michigan Transgenic Animal Core, Catherine Barth and Tiffany Newton for preliminary mouse evaluations, and Dr Michael Grotewiel, Dr Christopher Vlangos, Stephen Williams, and Lily Hoa Truong for critical reading of the manuscript. We thank the histopathology core at the Michigan State University and the Comparative Pathology Lab at UC Davis for mouse tissue and serum studies. This work was supported, in part, by NIH R01 HD38534 and by resources from Michigan State University and Virginia Commonwealth University.
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Girirajan, S., Patel, N., Slager, R. et al. How much is too much? Phenotypic consequences of Rai1 overexpression in mice. Eur J Hum Genet 16, 941–954 (2008). https://doi.org/10.1038/ejhg.2008.21
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DOI: https://doi.org/10.1038/ejhg.2008.21
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