TY - JOUR
T1 - Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral, and transcriptomic levels
AU - Montani, Caterina
AU - Balasco, Luigi
AU - Pagani, Marco
AU - Alvino, Filomena Grazia
AU - Barsotti, Noemi
AU - De Guzman, A. Elizabeth
AU - Galbusera, Alberto
AU - De Felice, Alessia
AU - Nickl-Jockschat, Thomas K.
AU - Migliarini, Sara
AU - Casarosa, Simona
AU - Lau, Pierre
AU - Mattioni, Lorenzo
AU - Pasqualetti, Massimo
AU - Provenzano, Giovanni
AU - Bozzi, Yuri
AU - Lombardo, Michael V.
AU - Gozzi, Alessandro
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - autism spectrum disorder
KW - autism spectrum disorder
UR - http://hdl.handle.net/10807/302921
UR - https://www.science.org/doi/10.1126/sciadv.adg1421
U2 - 10.1126/sciadv.adg1421
DO - 10.1126/sciadv.adg1421
M3 - Article
SN - 2375-2548
VL - 10
SP - 1
EP - 16
JO - Science advances
JF - Science advances
ER -