A truncating mutation of Magel2 in the rat modelled for the study of Schaaf-Yang and Prader-Willi syndromes alters select behavioral and physiological outcomes [article]

Derek L Reznik, Mingxiao V Yang, Pedro Albelda de la Haza, Antrix Jain, Melanie Spanjaard, Susanne Theiss, Christian P Schaaf, Anna Malovannaya, Theresa V Strong, Surabi Veeraragavan, Rodney C Samaco
2022 bioRxiv   pre-print
ABSTRACTTruncating mutations of the maternally imprinted, paternally expressed MAGEL2 gene are the predicted genetic cause of several rare neurodevelopmental disorders including Schaaf-Yang (SYS), Chitayat-Hall and Opitz Trigonocephaly C syndromes. MAGEL2 is also deleted or inactivated in Prader-Willi syndrome (PWS). Previous studies in mice have utilized Magel2 gene deletion models to examine the consequences of its absence. In this study, we report the generation, molecular validation, and
more » ... notypic characterization of a novel rat model with a truncating Magel2 mutation generating a mutant peptide sequence more closely modeling variants associated with SYS-causing mutations. Within the hypothalamus, a brain region wherein mouse and human MAGEL2 is paternally-expressed, we demonstrate at the level of transcript and peptide detection that Magel2 in the rat exhibits a paternal, parent-of-origin effect. In the evaluation of behavioral features across several domains, juvenile Magel2 mutant rats display select 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 for specific behavioral outcome measures. We conclude that our comprehensive analysis demonstrating impairments across multiple domains demonstrates the tractability of this model system for the study of truncating MAGEL2 mutations.
doi:10.1101/2022.08.09.503377 fatcat:4gtcwswkvzgepgjjtrl7ehlf3a