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dc.contributor.advisorHowell, Brian
dc.contributor.authorLammert, Dawn
dc.date.accessioned2021-06-10T14:43:35Z
dc.date.available2021-06-10T14:43:35Z
dc.date.issued2017
dc.identifier.urihttp://hdl.handle.net/20.500.12648/1754
dc.description.abstractAutism spectrum disorder (ASD) affects approximately 1 in 45 people, and is characterized by deficits in social communication and repetitive behaviors. Sequencing advancements have enabled the identification of numerous candidate genes, but precisely how these genes contribute to ASD remains largely unknown. RELNis consistently implicated as a candidate gene for autism. The encoded secreted glycoprotein, Reelin is important for proper brain developmental and postnatal synapse function. Here we examine the molecular and cellular consequences of the de novo RELNmutation R2290C. This mutation falls in a conserved arginine-amino acid-arginine (RXR) motif that is found within the Reelin subrepeat structure. Several other ASD patient mutations fall with in this consensus and all examined reduce Reelin secretion. Based on this we tested two hypothesis: (1) that the mutations reduce Reelin signaling and (2) that they have a gain-of-function consequence, such as ER stress. Using an engineered cell line with a heterozygous RELNR2290C mutation and the RELN Orleans (Orl) mouse line that produces nearly full length Reelin that is defective for secretion, we found evidence for both increased Dab1 and increased PDIA1 expression. Since, like most genes implicated in ASD RELNlikely acts in a multifactorial manner, we investigated whether second site mutations might contribute to ASD-related behaviors. Towards this end we crossed the heterozygous Orl and Shank3b mice to model two hits that are present in at least one ASD proband. We found that the resulting double heterozygousmice had impaired socialization and altered ultrasonic vocalizations. Furthermore, forebrain and cerebellar lysates showed increased PSD-95, identifying a potentially common mechanism and therapeutic target for ASD. These studies are the first to investigate the biological relevance of RELNcoding mutations in ASD.en_US
dc.language.isoen_USen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectRELNen_US
dc.subjectGENEen_US
dc.subjectAUTISM SPECTRUM DISORDERen_US
dc.subjectASDen_US
dc.titleRELN AS A CANDIDATE GENE FOR AUTISM SPECTRUM DISORDER (ASD)en_US
dc.typeDissertationen_US
dc.description.versionNAen_US
refterms.dateFOA2021-06-10T14:43:36Z
dc.description.institutionUpstate Medical Universityen_US
dc.description.departmentNeuroscience and Physiologyen_US
dc.description.degreelevelPhDen_US
dc.identifier.oclc1035420068


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International