Rare Schizophrenia-Associated Kalirin Variants: Possible Mechanistic Links to Cortical Neuronal Pathology

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Mounting evidence indicates that known schizophrenia susceptibility genes regulate dendritic spines supports the model that perturbations in the molecular network underlying spine plasticity are crucially involved in the pathogenesis of schizophrenia. The Rac1- and RhoA-guanine nucleotide exchange factor (GEF) kalirin is critical for spine morphogenesis on cortical pyramidal neurons, and postmortem studies have revealed altered kalirin expression in schizophrenia patients. Here I sought to identify rare missense single nucleotide variants (SNVs) in the KALRN gene region that encodes one of its gene product’s catalytic domains, and identified one in a schizophrenia patient and his sibling with major depressive disorder. The D1338N substitution significantly diminished the protein's ability catalyze the activation of Rac1. Contrary to wildtype kalirin-7, kalirin-7-D1338N failed to increase spine size and density. Both subjects carrying the SNV displayed reduced cortical volume in the superior temporal sulcus (STS), a region implicated in schizophrenia. Consistent with this, mice with reduced kalirin expression showed reduced neuropil volume in the rodent homolog of the STS. These data suggest that single amino acid changes in proteins involved in dendritic spine function can have significant effects on the structure and function of the cerebral cortex. Following this investigation, I turned my attention to another missense SNV, kalirin-9-P2255T, which displays a penetrance greatly exceeds that of previously identified schizophrenia-associated SNVs. Overexpression of kalirin-9-P2255T leads to diminished basal dendritic branching and dendritic spine size in cultured primary cortical pyramidal neurons, as compared to wildtype kalirin-9. The P2255T SNV directly affected kalirin-9 protein function, leading to increased RhoA activation, but had no effect on Rac1. Remarkably, consistent with human postmortem findings, I found that kalirin-9-P2255T protein levels were higher than those of wildtype kalirin-9. This increase was due to increased mRNA stability of the kalirin-9-P2255T transcript without changes to protein stability, with this SNV predicted to alter mRNA structure. When analyzed together, increased intrinsic RhoA-GEF catalytic activity combined with increased mRNA expression lead to an even greater net activation of RhoA, a protein known to negatively impact dendrites and spines. Taken together, my data reveal a novel mechanism for disease-associated SNVs and provide a platform for modeling morphological changes in mental disorders."]

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  • 10/08/2019
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