Functional Characterization of ASD-Associated EEF1A2 Mutations in Human Neurons
Abstract
Dysregulated protein synthesis has been implicated in both human genetic studies of autism spectrum disorder (ASD) and in mouse models of both syndromic and nonsyndromic ASD. There are three steps in involved in the regulation of protein synthesis: initiation, elongation, and termination. The majority of the regulation of protein synthesis takes place at the initiation step, and genes that encode proteins in regulation of this step have been linked to ASD. There also are syndromic and nonsyndromic forms of ASD that have been linked to the elongation step of protein synthesis. For example, the fragile X syndrome (FXS) is the leading single-gene cause of ASD, and fragile X mental retardation protein (FMRP), the protein missing in FXS, has been shown to be important for regulation of elongation. Recently, it has been shown that patients with mutations in EEF1A2, a gene that encodes a protein that regulates the elongation step of protein synthesis, develop ASD, intellectual disability, and epilepsy. Although there is a mouse model that reduces the expression of eEF1A2, it does not recapitulate the altered brain function observed in humans with EEF1A2 mutations. Therefore, we proposed to generate human neurons that will express of the three most common ASD-associated mutations. We will then characterize the neurons and determine the impact of each EEF1A2 mutation on protein synthesis, as well as the morphology, function, and communication of the neurons. We also will identify the proteins that are made improperly due to disruption of each of these three genes. Our proposed studies are likely to result in novel early diagnosis measures and future treatment options for patients with ASD caused by EEF1A2 mutations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110247
Entities
People
- Eric Klann
Organizations
- New York University
- United States Army