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J Neurochem DOI:10.1111/jnc.14045

The de novo autism spectrum disorder RELN R2290C mutation reduces Reelin secretion and increases protein disulfide isomerase expression.

Publication TypeJournal Article
Year of Publication2017
AuthorsLammert, DB, Middleton, FA, Pan, J, Olson, EC, Howell, BW
JournalJ Neurochem
Date Published2017 Jul
KeywordsAnimals, Autism Spectrum Disorder, Cell Adhesion Molecules, Neuronal, Cell Differentiation, Cerebellum, Extracellular Matrix Proteins, Gene Expression Regulation, Enzymologic, Humans, Mice, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins, Protein Disulfide-Isomerases, Retinoid X Receptors, RNA Editing, Serine Endopeptidases

Despite the recent identification of over 40 missense heterozygous Reelin gene (RELN) mutations in autism spectrum disorder (ASD), none of these has been functionally characterized. Reelin is an integral signaling ligand for proper brain development and post-natal synapse function - properties likely disrupted in ASD patients. We find that the R2290C mutation, which arose de novo in an affected ASD proband, and other analogous mutations in arginine-amino acid-arginine domains reduce protein secretion. Closer analysis of RELN R2290C heterozygous neurospheres reveals up-regulation of Protein Disulfide Isomerase A1, best known as an endoplasmic reticulum-chaperone protein, which has been linked to neuronal pathology. This effect is recapitulated in a heterozygous RELN 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 ASD risk.


Alternate JournalJ. Neurochem.
PubMed ID28419454
PubMed Central IDPMC6091860
Grant ListF31 NS086731 / NS / NINDS NIH HHS / United States
R01 NS073662 / NS / NINDS NIH HHS / United States
R21 MH099448 / MH / NIMH NIH HHS / United States