A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness

Russell, Theron A.; Blizinsky, Katherine D.; Cobia, Derin; Cahill, Michael E.; Xie, Zhong; Sweet, Robert A.; Duan, Jubao; Gejman, Pablo V.; Wang, Lei; Csernansky, John G.; Penzes, Peter

doi:10.1038/ncomms5858

Cited by 33 publications

(33 citation statements)

References 73 publications

(109 reference statements)

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“…In vitro expression of mutated kalirin-7 had reduced ability to catalyse the activation of Rac1 and did not cause the increases in spine size and density induced by expression of wild type kalirin-7. Of interest, both humans carrying the mutation demonstrated reductions in volume of superior temporal sulcus cortex, a region implicated in schizophrenia, while mice with reduced kalirin expression had reduced volume in the homologous region[75]. …”

Section: Possible Causes Of Dendritic Spine Loss In Schizophreniamentioning

confidence: 99%

Dendritic spine alterations in schizophrenia

Moyer

Shelton

Sweet

2015

Neuroscience Letters

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159

125

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Schizophrenia is a chronic illness affecting approximately 0.5–1% of the world’s population. The etiology of schizophrenia is complex, including multiple genes and contributing environmental effects that adversely impact neurodevelopment. Nevertheless, a final common result, present in many subjects with schizophrenia, is impairment of pyramidal neuron dendritic morphology in multiple regions of the cerebral cortex. In this review we summarize the evidence of reduced dendritic spine density and other dendritic abnormalities in schizophrenia, evaluate current data that informs the neurodevelopment timing of these impairments, and discuss what is known about possible upstream sources of dendritic spine loss in this illness.

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Section: Possible Causes Of Dendritic Spine Loss In Schizophreniamentioning

confidence: 99%

Dendritic spine alterations in schizophrenia

Moyer

Shelton

Sweet

2015

Neuroscience Letters

Self Cite

159

125

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“…For example, gene variations of ARHGEF6 (Cdc42/Rac1 guanine nucleotide exchange factor [GEF]) (Kutsche et al, ), PAK3 (the downstream effector for Rac/Cdc42 GTPases) (Allen et al, ) and oligophrenin‐1 (Rho GTPase activating protein [GAP]) (Billuart et al, ) have been identified in patients with X‐linked intellectual disability. Moreover, the association of Rac1‐GEF KALIRIN with schizophrenic patients has been found (Kushima et al, ; Russell et al, ).…”

Section: Introductionmentioning

confidence: 99%

Rho family GTPases, Rac and Cdc42, control the localization of neonatal dentate granule cells during brain development

et al. 2018

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The hippocampus is generally considered as a brain center for learning and memory. We have recently established an electroporation‐mediated gene transfer method to investigate the development of neonatal dentate granule cells in vivo. Using this new technique, we introduced knockdown vectors against Rac1 small GTPase into precursors for dentate granule cells at postnatal day 0. After 21 days, Rac1‐deficient cells were frequently mispositioned between the granule cell layer (GCL) and hilus. About 60% of these mislocalized cells expressed a dentate granule cell marker, Prox1. Both the dendritic spine density and the ratio of mature spine were reduced when Rac1 was silenced. Notably, the deficient cells have immature thin processes during migrating in the early neonatal period. Knockdown of another Rac isoform, Rac3, also resulted in mislocalization of neonatally born dentate granule cells. In addition, knockdown of Cdc42, another Rho family protein, also caused mislocalization of the cell, although the effects were moderate compared to Rac1 and 3. Despite the ectopic localization, Rac3‐ or Cdc42‐disrupted mispositioned cells expressed Prox1. These results indicate that Rho signaling pathways differentially regulate the proper localization and differentiation of dentate granule cells.

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“…Genetic studies implicate the KALRN gene in schizophrenia, stroke, autism, substance abuse and intellectual disability 1-9 . KALRN is highly conserved from C. elegans and D. melanogaster to humans 10 .…”

Section: Introductionmentioning

confidence: 99%

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

Miller¹,

Yan²,

Machida³

et al. 2017

ACS Chem. Neurosci.

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Kalirin7 (Kal7), a postsynaptic Rho GDP/GTP exchange factor (RhoGEF), plays a crucial role in long term potentiation and in the effects of cocaine on behavior and spine morphology. The KALRN gene has been linked to schizophrenia and other disorders of synaptic function. Mass spectrometry was used to quantify phosphorylation at 26 sites in Kal7 from individual adult rat nucleus accumbens and prefrontal cortex before and after exposure to acute or chronic cocaine. Region- and isoform-specific phosphorylation was observed along with region-specific effects of cocaine on Kal7 phosphorylation. Evaluation of the functional significance of multi-site phosphorylation in a complex protein like Kalirin is difficult. With the identification of five tyrosine phosphorylation (pY) sites, a panel of 71 SH2 domains was screened, identifying subsets that interacted with multiple pY sites in Kal7. In addition to this type of reversible interaction, endoproteolytic cleavage by calpain plays an essential role in long-term potentiation. Calpain cleaved Kal7 at two sites, separating the N-terminal domain, which affects spine length, and the PDZ binding motif from the GEF domain. Mutations preventing phosphorylation did not affect calpain sensitivity or GEF activity; phosphomimetic mutations at specific sites altered protein stability, increased calpain sensitivity and reduced GEF activity.

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A sequence variant in human KALRN impairs protein function and coincides with reduced cortical thickness

Cited by 33 publications

References 73 publications

Dendritic spine alterations in schizophrenia

Dendritic spine alterations in schizophrenia

Rho family GTPases, Rac and Cdc42, control the localization of neonatal dentate granule cells during brain development

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

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