Journal article
Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral, and transcriptomic levels
Science advances, Vol.10(28), eadg1421
07/12/2024
DOI: 10.1126/sciadv.adg1421
PMCID: PMC11244557
PMID: 38996019
Abstract
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 sex-differential mechanisms.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 sex-differential mechanisms.
Details
- Title: Subtitle
- Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral, and transcriptomic levels
- Creators
- Caterina Montani - Center for Neuroscience and Cognitive SystemsLuigi Balasco - University of TrentoMarco Pagani - Center for Neuroscience and Cognitive SystemsFilomena Grazia Alvino - Center for Neuroscience and Cognitive SystemsNoemi Barsotti - University of PisaA Elizabeth de Guzman - Center for Neuroscience and Cognitive SystemsAlberto Galbusera - Center for Neuroscience and Cognitive SystemsAlessia de Felice - Center for Neuroscience and Cognitive SystemsThomas K Nickl-JockschatSara Migliarini - University of PisaSimona Casarosa - University of TrentoPierre Lau - Italian Institute of TechnologyLorenzo Mattioni - University of TrentoMassimo Pasqualetti - University of PisaGiovanni Provenzano - University of TrentoYuri Bozzi - University of TrentoMichael V Lombardo - Center for Neuroscience and Cognitive SystemsAlessandro Gozzi - Center for Neuroscience and Cognitive Systems
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.10(28), eadg1421
- DOI
- 10.1126/sciadv.adg1421
- PMID
- 38996019
- PMCID
- PMC11244557
- NLM abbreviation
- Sci Adv
- ISSN
- 2375-2548
- eISSN
- 2375-2548
- Language
- English
- Date published
- 07/12/2024
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984656631802771
Metrics
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