Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes

Molecular Autism

Matthew C. Judson¹  Benjamin D. Philpot¹  Johanna Hakonen²  Mireia Bernabé Kleijn²  Geeske M. van Woerden²  Ype Elgersma²  Monica Sonzogni²  Sara Silva-Santos² 

[1] 0000 0001 1034 1720, grid.410711.2, Neuroscience Center, Department of Cell Biology and Physiology, and Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA;000000040459992X, grid.5645.2, Department of Neuroscience and the ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, 3015 CN, Rotterdam, The Netherlands;

关键词: Ube3a;    Angelman syndrome;    Mouse model;    Seizure;    Autism spectrum disorder;    Phenotype;   

DOI  :  10.1186/s13229-019-0277-1

来源: publisher

【 摘 要 】

BackgroundAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations affecting UBE3A gene expression. Previous studies in mice revealed distinct critical periods during neurodevelopment in which reactivation of Ube3a gene expression can prevent the onset of behavioral deficits. Whether UBE3A is required for brain function throughout life is unknown. Here, we address the importance of maintaining UBE3A expression after normal brain development.FindingsUsing a conditional mouse, we deleted the Ube3a gene at three ages spanning brain maturation. We assessed the consequences of Ube3a gene deletion by testing the mice in behavioral tasks previously shown to produce robust phenotypes in AS model mice. Early embryonic deletion of Ube3a recapitulated all behavioral deficits of AS mice. In contrast, Ube3a gene deletion at 3 or 12 weeks of age did not have a significant effect on most behavioral tasks and did not increase seizure sensitivity.ConclusionsTaken together, these results emphasize that UBE3A critically impacts early brain development, but plays a more limited role in adulthood. Our findings provide important considerations for upcoming clinical trials in which UBE3A gene expression is reactivated and suggest that even transient UBE3A reinstatement during a critical window of early development is likely to prevent most adverse Angelman syndrome phenotypes. However, sustained UBE3A expression into adulthood is probably needed for optimal clinical benefit.

【 授权许可】

CC BY