Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes.
Monica Sonzogni, Johanna Hakonen, Mireia Bernabé Kleijn and 5 others
PMID 31143434WHAT IT FOUND
In mice, deleting Angelman-related Ube3a after early brain development caused few AS-like behavioural deficits, except forced-swim immobility and juvenile nest-building problems.
This does not show that human therapy timing can be changed.
Key findings
01When Ube3a was deleted in adult mice at 12 weeks, most tested behavioural deficits were absent, but forced-swim performance was impaired.
02Juvenile deletion at 3 weeks impaired forced-swim and nest-building performance, while other tested behaviours were unaffected.
03Embryonic deletion made 15/15 mice susceptible to audiogenic seizures, but juvenile deletion made 0/8 susceptible and adult deletion made 0/16 susceptible.
STILL TO COME
How it was doneWhat they found
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What it does not show
This is a mouse gene-deletion study, not a clinical trial in people with Angelman syndrome, so it cannot tell therapists how to time treatment in humans. The study deleted Ube3a after development; it did not test the proposed UBE3A reinstatement therapies, so it does not show whether starting, stopping, or sustaining such therapy would help patients. Tamoxifen-induced deletion may not have occurred in every cell, and a small remaining UBE3A expression could have influenced behaviour. Learning and memory behaviours were not assessed, although intellectual disability is a major human feature of Angelman syndrome. Some behavioural tests, such as marble burying and nest building, have limited face validity for human Angelman syndrome features. The authors state that the first 3 weeks of mouse postnatal development may not translate directly to human brain development.
Declared interests
The supplied text does not include an author conflict-of-interest declaration. Publication types indicate NIH extramural and non-U.S. government research support.
The easy way to misread this
Do not read this as evidence that Angelman syndrome therapy can be delayed until after early development or stopped in adults. The study deleted Ube3a in mice, did not test reinstatement therapy in people, and found forced-swim deficits after adult deletion, plus a nest-building deficit after juvenile deletion.