The de novo autism spectrum disorder RELN R2290C mutation reduces Reelin secretion and increases protein disulfide isomerase expression.
The de novo autism spectrum disorder RELN R2290C mutation reduces Reelin secretion and increases protein disulfide isomerase expression.
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DOI：
10.1111/jnc.14045
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发表时间：
2017-07
影响因子：
4.7
通讯作者：
Howell BW
中科院分区：
文献类型：
--
作者：
Lammert DB;Middleton FA;Pan J;Olson EC;Howell BW
Despite the recent identification of over 40 missense heterozygous RELN mutations in ASD, none of these has been functionally characterized. Reelin is an integral signaling ligand for proper brain development and postnatal 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 RXR domains reduce protein secretion. Closer analysis of RELN R2290C heterozygous neurospheres reveals upregulation of Protein Disulfide Isomerase A1, best known as an ER-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.
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