Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, CNCS@UNITN, Rovereto, Italy.
Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
Sci Adv. 2024 Jul 12;10(28):eadg1421. doi: 10.1126/sciadv.adg1421.
Genomic mechanisms enhancing risk in males may contribute to sex bias in autism. The ubiquitin protein ligase E3A gene () affects cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of 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 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 overdosage can contribute to sex bias in neurodevelopmental conditions via influence on sex-differential mechanisms.
增强男性风险的基因组机制可能导致自闭症的性别偏见。泛素蛋白连接酶 E3A 基因（UBE3A）通过控制蛋白质周转和作为类固醇激素受体的转录共激活因子来影响细胞内稳态。染色体 15q11-13 区域的重复或三倍性导致 1%至 2%的自闭症病例。在这里，我们检验了这样一种假设，即 UBE3A 基因剂量的增加可能以性别偏向的方式影响自闭症相关表型。我们发现，具有额外 Ube3a 拷贝的小鼠在大脑连接组学和自闭症相关行为上表现出性别偏向效应。这些效应与自闭症相关基因的转录失调有关，也与 15q 重复和自闭症患者中差异表达的基因有关。UBE3A 基因剂量的增加还影响 X 染色体上基因、受性激素影响的基因以及受转录因子性别差异调控的基因的表达。这些结果表明，UBE3A 基因剂量过高可能通过影响性别差异机制导致神经发育障碍的性别偏见。
