Search

Genomic mechanisms enhancing risk in males may contribute to sex bias in autism. The ubiquitin protein ligase E3A gene (Ube3a) affects cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal region 15q11-13 causes 1 to 2% of autistic cases. Here, we test the hypothesis that increased dosage of Ube3a may influence autism-relevant phenotypes in a sex-biased manner. We show that mice with extra copies of Ube3a exhibit sex-biasing effects on brain connectomics and autism-relevant behaviors. These effects are associated with transcriptional dysregulation of autism-associated genes, as well as genes differentially expressed in 15q duplication and in autistic people. Increased Ube3a dosage also affects expression of genes on the X chromosome, genes influenced by sex steroid hormone, and genes sex-differentially regulated by transcription factors. These results suggest that Ube3a overdosage can contribute to sex bias in neurodevelopmental conditions via influence on sexdifferential mechanisms. [ABSTRACT FROM AUTHOR]

This article, published in Frontiers in Psychiatry, discusses the need for further research into neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disabilities. The article highlights recent studies that have identified gene variants associated with NDDs, indicating the genetic complexity of these disorders. Additionally, the article explores the role of neuroinflammatory mechanisms and environmental factors, such as early life adversities, in the development of NDDs. The authors emphasize the importance of a multidisciplinary approach to understanding NDDs and suggest that this knowledge could lead to novel therapeutic strategies. [Extracted from the article]