Abstract
Smith-Magenis syndrome is a complex genomic disorder in which a majority of individuals are obese by adolescence. While an interstitial deletion of chromosome 17p11.2 is the leading cause, mutation or deletion of the RAI1 gene alone results in most features of the disorder. Previous studies have shown that heterozygous knockout of Rai1 results in an obese phenotype in mice and that Smith-Magenis syndrome mouse models have a significantly reduced fecundity and an altered transmission pattern of the mutant Rai1 allele, complicating large, extended studies in these models. In this study, we show that breeding C57Bl/6J Rai1+/− mice with FVB/NJ to create F1 Rai1+/− offspring in a mixed genetic background ameliorates both fecundity and Rai1 allele transmission phenotypes. These findings suggest that the mixed background provides a more robust platform for breeding and larger phenotypic studies. We also characterized the effect of dietary intake on Rai1+/− mouse growth during adolescent and early adulthood developmental stages. Animals fed a high carbohydrate or a high fat diet gained weight at a significantly faster rate than their wild type littermates. Both high fat and high carbohydrate fed Rai1+/− mice also had an increase in body fat and altered fat distribution patterns. Interestingly, Rai1+/− mice fed different diets did not display altered fasting blood glucose levels. These results suggest that dietary regimens are extremely important for individuals with Smith- Magenis syndrome and that food high in fat and carbohydrates may exacerbate obesity outcomes.
Highlights
Smith-Magenis syndrome (SMS, OMIM 182290) is a complex genomic disorder characterized by skeletal and craniofacial anomalies, intellectual disability, sleep abnormalities, developmental delay, and a myriad of neurological and behavioral issues, including self-injurious and attention-seeking behaviors [1]
Rai1+/2 mice when bred in the congenic C57Bl/6J background produced an average of 4 animals per litter; C57Bl/6J Rai1+/2 mice when mated to wild type FVB/NJ genetic background saw a significant improvement in fecundity (P, 0.0001) with an average of 10 pups per litter (Figure 1A)
C57Bl/6J mice bred into the FVB/NJ background produced significantly more wild type (P = 0.0075) and Rai1+/2 (P,0.0001) pups compared to a pure C57Bl/6J background (Figure 1B), with an equal distribution of wild type and Rai1+/2 pups (Figure 1B)
Summary
Smith-Magenis syndrome (SMS, OMIM 182290) is a complex genomic disorder characterized by skeletal and craniofacial anomalies, intellectual disability, sleep abnormalities, developmental delay, and a myriad of neurological and behavioral issues, including self-injurious and attention-seeking behaviors [1]. Individuals with SMS can have a wide range of phenotypic variability [5,6], likely due to a variety of genetic factors such as natural genetic variation modifying the phenotype, complex epistatic interactions, and the modifying effects of the environment. Previous work using mouse models has sought to understand the role of Rai in SMS by characterizing the functional effects of the gene on an array of phenotypic measures; the etiology and pathogenicity of altered Rai expression during development and on homeostatic cellular mechanisms remains unclear. SMS mouse models display a range of behavioral abnormalities, variable penetrance of craniofacial defects, obesity, and reduced fecundity [7,8,9]. The variability of some phenotypic features has been associated with modifier alleles that either mask or exacerbate particular phenotypic outcomes [8,10], while congenic strains have been shown to display altered Mendelian transmission of mutant Rai alleles [10]
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