Sex-dependent sensory phenotypes and related transcriptomic expression profiles are differentially affected by Angelman syndrome. Mus musculus

Background: Angelman syndrome (AS) is a genetic neuropsychiatric disorder caused by lack of Ube3A protein expression, which is an E3-ubiquitin ligase. This syndrome entails autism, mental retardation, lack of speech, motor deficits and susceptibility for seizures. AS is equally prevalent in males and females, but until now there was no thorough investigation of how sex affects the syndrome phenomenology.Methods: In the herein study we thoroughly characterized many cognitive and neurological phenotypes of AS mice and their wild-type littermates by utilizing a wide array of behavioral paradigms. The data acquired were analyzed with respect to sex effects. In addition, we generated an mRNA-sequencing dataset and analyzed this coding transcriptome expression profiles according to genotype and sex.Results: We identified that in some neurological and cognitive aspects, especially in tests that estimate the sensory perception, AS mice either lack the male to female differences observed in wild-type littermates, or even show opposed differences. However, simple motor phenotypes do not show any male to female variation between WT and AS mice. In addition, by utilizing the mRNA sequencing we identified many genes differentially regulated in two sexes, some of them even with opposite differential expression profiles in AS mice compared to WT littermates, among them genes known to be estrogen-dependent.Conclusions: These observed differences in sex-dependent neurological and cognitive phenotypes in AS mice strengthen the evidence for a molecular crosstalk between Ube3A protein and sex hormone receptors or their elicited pathways. We believe that understanding these interactions are important for revealing the full effects of Ube3A deletion, beyond its E3-ligase activity. These findings support future development of better and more comprehensive treatment strategies.