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Reelin is an integral signaling ligand for proper brain development and post\u2010natal synapse function \u2013 properties likely disrupted in <jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content> patients. We find that the R2290C mutation, which arose <jats:italic>de novo<\/jats:italic> in an affected <jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content> proband, and other analogous mutations in arginine\u2010amino acid\u2010arginine domains reduce protein secretion. Closer analysis of <jats:italic><jats:styled-content style=\"fixed-case\">RELN<\/jats:styled-content><\/jats:italic> R2290C heterozygous neurospheres reveals up\u2010regulation of Protein Disulfide Isomerase A1, best known as an endoplasmic reticulum\u2010chaperone protein, which has been linked to neuronal pathology. This effect is recapitulated in a heterozygous <jats:italic><jats:styled-content style=\"fixed-case\">RELN<\/jats:styled-content><\/jats:italic> mouse mutant that is characterized by defective Reelin secretion. These findings suggest that both a deficiency in Reelin signaling and pathologic impairment of Reelin secretion may contribute to <jats:styled-content style=\"fixed-case\">ASD<\/jats:styled-content> risk.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14045-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14045","type":"journal-article","created":{"date-parts":[[2017,4,17]],"date-time":"2017-04-17T18:12:46Z","timestamp":1492452766000},"page":"89-102","source":"Crossref","is-referenced-by-count":28,"title":["The <i>de novo<\/i> autism spectrum disorder <i><scp>RELN<\/scp><\/i> R2290C mutation reduces Reelin secretion and increases protein disulfide isomerase 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