Angelman syndrome (AS) is characterized by severe cognitive impairment, loss of speech, movement disabilities, inappropriate laughter, epilepsy, and abnormal electroencephalogram. Currently, there is no treatment for it. This disorder has been studied at Texas Children’s/Baylor College of Medicine for over 20 years. Our researchers and epileptologists have made several crucial contributions that have advanced our knowledge and have led to a potential treatment for this epileptic syndrome.
Seminal research conducted in the laboratory of Dr. Arthur Beaudet, professor at Baylor College of Medicine, led to the following important discoveries about AS -
- Mutations in UBE3A, a gene that encodes for an ubiquitin ligase on chromosome 15q11-13, are the cause of AS. Learn more
- Loss of a maternal-specific copy of Ube3a gene from certain brain regions, such as the hippocampus and cerebellum, is responsible for AS. The reason being UBE3A gene is genetically imprinted such that only the copy inherited from the mother is expressed and when that copy is not fully functionally, it results in AS. Learn more
- In mice, an antisense transcript, Ube3a-ATS, transcribed by an atypical RNA polymerase (RNAP) II, represses the expression ofUbe3a on the paternal chromosome. Learn more
- Truncation of Ub3a-ATS un-silences the paternal chromosome and allows the paternal copy of Ube3a to also be expressed. This reversed most of the symptoms in the AS mice, including motor coordination defects, cognitive deficit, and impaired long-term potentiation. Learn more
- Anti-sense oligonucleotides against Ube3a-ATS can un-silence paternal Ube3a in neurons in vitro and in vivo. Using this strategy of targeting the non-coding RNA, researchers were able to partially restore the function of UBE3A protein in the neurons, which was sufficient to reverse the cognitive symptoms observed in Angelman syndrome mouse models. Learn more
A recent study from the laboratory of Dr. Anne Anderson, epileptologist at Texas Children’s Hospital and investigator at the Gordon and Mary Cain Pediatric Neurology Research Foundation Laboratories found that the genetic background of AS mouse models have a pronounced influence on the behavioral, EEG and seizure phenotypes of these animals. This has important implications for future studies in the context of screening novel therapeutics for AS patients. Learn more