In 1997, Dr. Art Beaudet at Baylor College of Medicine determined that the lack of UBE3A gene expression caused Angelman syndrome (AS). Part of his finding came from looking at individuals with a mutation in the UBE3A gene; wherein, he discovered that a deficiency in UBE3A contributes to the major clinical presentation of AS. As a graduate student working with Dr. Beaudet, Dr. Yong-Hui Jiang developed and characterized one of the most widely utilized Angelman syndrome mouse models currently available throughout the world.
However, natural history studies and observations from doctors and caregivers have shown that those with a deletion of UBE3A (rather than a mutation) in the region of Chromosome 15q11-q13, may have more severe symptoms of AS. These include seizures that may be more difficult to control, increased mobility, gross and fine motor challenges, a more severe communication impairment (Moncla, et. al., 1999), and some may have more severe feeding difficulties as well. Over 70% of individuals living with Angelman syndrome are thought to have a deletion on their maternal 15th chromosome.
For individuals with Angelman syndrome, a typical 6 Mb deletion is considered a “large deletion” of 15q11-q13. In addition to the missing UBE3A gene, individuals with a large deletion are missing other genes such as GABRB3, GABRA5, GABAG3, and CYFP1. These genes are thought to be important for various aspects of brain function, but since these individuals are only halploinsufficient, meaning they do have functional copies of these genes on the paternal 15th chromosome, it is unclear the impact these individual genes could have on their own. There are known individuals with a deletion or mutation of some of these other genes, not including UBE3A, that have none, or minimal, symptoms. Scientists theorize that the deletion of these “other” genes on the maternal 15th chromosome could be causing the increased symptom severity; however, specific symptoms have not yet been mapped to these specific genes. As we near a therapeutic targeting UBE3A specifically, we have focused our attention on some of these other genes to be able to ensure that we can understand how to ameliorate other symptoms that could remain after UBE3A reinstatement.
While larger deletion mouse models have been created in the past, currently the only currently viable Angelman syndrome mouse models are those with only the Ube3a gene deleted or mutated. FAST is now funding Dr. Yong-Hui Jiang, MD, PhD, Professor of Pediatrics and Neurobiology and Chief of Medical Genetics at the Yale University School of Medicine and his lab to create 2 large deletion mouse models. One will encompass the Ube3a gene, as well as the other commonly deleted genes such as GABRB3, GABRA5, GABAG3 andCYFIP1, which should approach the equivalent of approximately 6MB in size. The other model is one with all of the missing genes, except for Ube3a. The main objective of the proposed study is to produce and characterize a new lines of mouse models that recapitulate the large 15q11-q13 deletion and phenotypically characterize the difference in genotype with and without Ube3a reinstatement. This will allow investigators to focus on therapeutic targets not only for Ube3a but for the other haploinsufficient genes missing in the largest cohort of those living with Angelman syndrome, the deletion genotype. These 2 AS mouse models will enhance the capacity for future human preclinical studies. This work will serve as an important complement to the development of treatments that aim to reactive the expression of UBE3A from the paternal chromosome or deliver the normal copy of UBE3A to the brain.