Autism spectrum disorders (ASD) comprise a heterogeneous group of neurodevelopmental disorders characterized by complex genetic etiology. Mutations in human APBA2, which encodes for the neuronal adaptor protein Mint2, have been genetically linked to ASD patients. APBA2 maps to the distal portion of chromosome 15q13.1, a region commonly deleted in Prader-Willi and Angelman neurodevelopmental disorders and duplicated in cases of autism, making APBA2 an attractive candidate gene associated with autism. Seven novel nonsynonymous coding variants in APBA2 in ASD subjects have been identified, five of which were predicted to affect protein function; however, they have not been examined functionally. Mint2 belongs to a family of neuronal adaptor proteins that are important for synaptic function. Mint2 interacts directly with the cell adhesion protein neurexin-1α, as part of a multi-protein complex that acts as a facilitator of neurotransmitter release. Together, these data suggest that Mint2 plays an important role in neuronal function, and sequence variations in Mint2 may alter neuronal dysfunction associated with ASD.
This thesis examines a point mutation in Mint2, which changes a conserved asparagine residue to a serine (N723S) in the second PDZ domain of Mint2, which binds to neurexin-1α. We found the Mint2 N723S mutation did not affect the binding to neurexin-1α; however, it dramatically altered neurexin-1α stabilization and trafficking in HEK293T cells. While Mint2 wild type greatly increased neurexin-1α at the membrane, Mint2 N723S showed a decreased membrane level of neurexin-1α, indicating the steady-state surface expression of neurexin is affected by the Mint2 N723S mutation. Also, we found that Mint2 N723S decreased neurexin localization in axons and the presynaptic terminal in neurons, which correlated with a decrease in synaptogenesis and miniature event frequency in excitatory synapses in neurons. Together, these results suggest that Mint2 N723S leads to dysfunction in neuronal development, in part due to alterations in intracellular neurexin trafficking and altered synaptic function of Mint2, as potential mechanisms that contribute to ASD pathogenesis. / 2018-11-01T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/26508 |
| Date | 01 November 2017 |
| Creators | Lin, Ying |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NonCommercial-NoDerivatives 4.0 International, http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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