Characterization of Autism Susceptibility Genes on Chromosome 15q11-13

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DESCRIPTION (provided by applicant): Maternal duplication of chromosome 15q11-13 is the most common copy number variation causing autism spectrum disorder (ASD), present in 1-3% of all ASD cases. Importantly, paternal duplication does not cause ASD, suggesting that the causative gene(s) are imprinted. Of 40 genes in the chromosomal region, only UBE3A is expressed exclusively from the maternal chromosome in the brain. UBE3A, Angleman's syndrome (AS) gene, is an E3 ubiquitin ligase mutated to cause mental retardation, impaired speech, overly-social behavior, excess laughing, seizures and stereotyped facial features. Given the gene's role in causing this severe mental disorder, and the recent evidence implicating ubiquitin pathways in ASD pathophysiology, we hypothesize that Ube3a mediates ASD risk in 15q11-13 duplication. In order to study UBE3A function in brain, we obtained UBE3A maternal-deificent (knockout) mice, and generated novel mice harboring two extra copies of UBE3A, modeling isodicentric 15q disorder which shows a high prevalence of ASD. Importantly, we have shown that this idic15 mouse model displays a marked increase of brain protein ubiquitination. Based on the observed opposing symptoms of AS (15q11-13 deletion) and ASD (15q11-13 duplication), such as hyper- tonia vs hypo-tonia in infancy and hyper-social behavior vs. hypo-social behavior in early childhood, respectively, we predict that mice lacking Ube3a and overexpressing Ube3a will show opposing phenotypes which will highlight the normal function of UBE3A. The objectives of the current proposal are the following: 1) to demonstrate that UBE3A contributes to the ASD observed in children inheriting extra copies of 15q11-13 from their mother, and 2) to elucidate the cellular basis of these disorders and UBE3A function in neuronal circuit function. Towards this goal, we will first characterize behaviors directly relevant to ASD (social interaction, infant vocalization) and to neuropsychiatric disease (e.g., anxiety) in our novel overexpressing mice. Second, thalamic neurons express high levels of Ube3a, display reduced metabolic activity (FDG uptake) in ASD, and could underlie behavioral defects. Therefore, we will perform a comprehensive electrophysiology-based characterization of thalamic circuitry structure and function in both UBE3A overexpressing and deficent mice. Overall, we predict excess UBE3A will be sufficent to replicate many of the features of 15q11-13 ASD, defining a new genetic model of ASD. PUBLIC HEALTH RELEVANCE: The most common chromosomal abnormality that causes autism is duplication of chromosome 15q11- 13, which results in a child having too many copies of several genes. We will insert extra copies of a gene likely to be important in 15q duplication into mice, characterize the behavior of the mice, and investigate, on a molecular level, how these genes might lead to abnormal behaviors related to autism.