Sex-biasing influence of autism-associated <i>Ube3a</i> gene overdosage at connectomic, behavioral, and transcriptomic levels-Reference-Cited by-同舟云学术

Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral, and transcriptomic levels

Published:2024-07-12 Issue:28 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Montani Caterina¹^ORCID,Balasco Luigi²^ORCID,Pagani Marco¹³⁴^ORCID,Alvino Filomena Grazia¹^ORCID,Barsotti Noemi⁵^ORCID,de Guzman A. Elizabeth¹^ORCID,Galbusera Alberto¹^ORCID,de Felice Alessia¹,Nickl-Jockschat Thomas K.⁶⁷⁸^ORCID,Migliarini Sara⁵^ORCID,Casarosa Simona²⁹^ORCID,Lau Pierre¹⁰^ORCID,Mattioni Lorenzo²^ORCID,Pasqualetti Massimo⁵^ORCID,Provenzano Giovanni²^ORCID,Bozzi Yuri¹¹¹²^ORCID,Lombardo Michael V.¹³^ORCID,Gozzi Alessandro¹^ORCID

Affiliation:

1. Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, CNCS@UNITN, Rovereto, Italy.

2. Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.

3. Autism Center, Child Mind Institute, New York, NY, USA.

4. IMT School for Advanced Studies, Lucca, Italy.

5. Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, Pisa, Italy.

6. Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany.

7. German Center for Mental Health (DZPG), partner site Halle-Jena-Magdeburg, Germany.

8. Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Halle-Jena-Magdeburg, Germany.

9. Centre for Medical Sciences (CISMed), University of Trento, Trento, Italy.

10. Istituto Italiano di Tecnologia, Center for Human Technologies, Genova, Italy.

11. Center for Mind/Brain Sciences (CIMeC), University of Trento, Rovereto, Italy.

12. CNR Neuroscience Institute, Pisa, Italy.

13. Laboratory for Autism and Neurodevelopmental Disorders, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, CNCS@UNITN, Rovereto, Italy.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adg1421

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