Previous studies in mice have utilized Magel2 gene deletion models to examine the consequences of its absence. We report the generation, molecular validation, and phenotypic characterization of a novel rat model with a truncating Magel2 mutation modeling variants associated with SYS-causing mutations. Within the hypothalamus, a brain region wherein human MAGEL2 is paternally-expressed, we demonstrate at the level of transcript and peptide detection that rat Magel2 exhibits a paternal, parent-of-origin effect. Evaluating behavioral features across several domains, juvenile Magel2 mutant rats display alterations in anxiety-like behavior and sociability measures. Moreover, the analysis of peripheral organ systems detected alterations in body composition, cardiac structure and function, and breathing irregularities in Magel2 mutant rats. Several of these findings are concordant with reported mouse phenotypes, signifying the conservation of MAGEL2 function across rodent species. Our comprehensive analysis revealing impairments across multiple domains demonstrates the tractability of this model system for the study of truncating MAGEL2 mutations.

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