Magel2 truncation alters select behavioral and physiological outcomes in a rat model of Schaaf-Yang syndrome

Abstract

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.

Hormonal Imbalances in Prader–Willi and Schaaf–Yang Syndromes Imply the Evolution of Specific Regulation of Hypothalamic Neuroendocrine Function in Mammals

“…The syntenic PWS regions on chromosome 7C in mice and chromosome 1 in rats are generally organized and imprinted similarly to the human PWS region (Figure 1B,C) [3,12,24,25]. The positional conservation and gene organization, including the imprinting pattern between mice, rats, and humans, imply evolutionarily conserved physiological functions of this locus in mammals.…”

“…Interestingly, pheromone detection in mice is the result of a direct neural connection between the main olfactory epithelium and the hypothalamic GnRH neurons [182,206,207]. Some behavioral phenotypes were also recapitulated in the Magel2 m+/p− rat (Figure 3B); however, there are several interspecies differences that need to be further investigated to completely understand the role of MAGEL2 and how to overcome its deficiency in patients [12]. Overall, these studies indicate that the loss of MAGEL2 expression contributes to the reproductive deficiencies observed in PWS, as well as many other clinical features [21].…”

“…Orange and green color-paternally expressed genes; purple color-maternally expressed genes; BP-break point; IC-imprinting center. The figure was generated based on [10][11][12]. Gene map of PWS loci in humans (A), mouse (B), and rat (C) models with deletions reported in each species.…”

“…Orange and green color-paternally expressed genes; purple color-maternally expressed genes; BP-break point; IC-imprinting center. The figure was generated based on [10][11][12].…”

Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes

“… 42 In addition, rats with paternal Magel2 truncation exhibit changes in body composition, cardiac structure and function, breathing, as well as sociability and anxiety-like behavior, also observed in SYS-affected individuals. 43 …”