DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription.

ABSTRACT: Disrupted-In-Schizophrenia 1 (DISC1), a strong genetic candidate for psychiatric illness, encodes a multicompartmentalized molecular scaffold that regulates interacting proteins with key roles in neurodevelopment and plasticity. Missense DISC1 variants are associated with the risk of mental illness and with brain abnormalities in healthy carriers, but the underlying mechanisms are unclear. We examined the effect of rare and common DISC1 amino acid substitutions on subcellular targeting. We report that both the rare putatively causal variant 37W and the common variant 607F independently disrupt DISC1 nuclear targeting in a dominant-negative fashion, predicting that DISC1 nuclear expression is impaired in 37W and 607F carriers. In the nucleus, DISC1 interacts with the transcription factor Ac

SUBMITTER: Malavasi EL 

PROVIDER: S-EPMC3363331 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature