ArticleBiological psychiatry2018
A Schizophrenia-Linked KALRN Coding Variant Alters Neuron Morphology, Protein Function, and Transcript Stability.
Article in Biological psychiatry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Increased RHOA expression in peripheral blood mononuclear cells of patients with acute schizophrenia.Molecular biology reports · 2026Article
- New insights into neurodevelopmental disorders by whole genome sequencing of 100 families from Italy.NPJ genomic medicine · 2026Article
- Amyloid beta pathology induces astrocytic pTDP-43 mislocalization and disrupts TDP-43-regulated cryptic exon transcripts.Frontiers in aging neuroscience · 2026Article
- Comprehensive profiling of transcription factors for reprogramming human astrocytes to neuronal cells through endogenous CRISPR-based gene activation.bioRxiv : the preprint server for biology · 2025Article
- Cytoskeletal control in adult microglia is essential to restore neurodevelopmental synaptic and cognitive deficits.Science advances · 2025Article
- Metagenome-based characterization of the gut virome in patients with schizophrenia.Journal of translational medicine · 2025Article
- Gastrodin Mitigates Ketamine-Induced Inhibition of F-Actin Remodeling and Cell Migration by Regulating the Rho Signaling Pathway.Biomedicines · 2025Article
- Identification and characterization of human KALRN mRNA and Kalirin protein isoforms.Cerebral cortex (New York, N.Y. : 1991) · 2024Article
- Are Methylation Patterns in theInternational journal of molecular sciences · 2024Article
- Genomic and Reverse Translational Analysis Discloses a Role for Small GTPase RhoA Signaling in the Pathogenesis of Schizophrenia: Rho-Kinase as a Novel Drug Target.International journal of molecular sciences · 2023Review
- A Novel Cis-Regulatory lncRNA,Non-coding RNA · 2023Article
- Impaired XK recycling for importing manganese underlies striatal vulnerability in Huntington's disease.The Journal of cell biology · 2022Article
- Review
- A developmental delay linked missense mutation in Kalirin-7 disrupts protein function and neuronal morphology.Frontiers in molecular neuroscience · 2022Article
- A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Review
- A Human-Specific Schizophrenia Risk Tandem Repeat Affects Alternative Splicing of a Human-Unique Isoform AS3MTd2d3 and Mushroom Dendritic Spine Density.Schizophrenia bulletin · 2021Article
- Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility.Human genome variation · 2020Article
- A lead candidate functional single nucleotide polymorphism within the WARS2 gene associated with waist-hip-ratio does not alter RNA stability.Biochimica et biophysica acta. Gene regulatory mechanisms · 2020Article
- SULT4A1 Modulates Synaptic Development and Function by Promoting the Formation of PSD-95/NMDAR Complex.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
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10 authors.
Funding
Abstract
backgroundLarge-scale genetic studies have revealed that rare sequence variants, including single nucleotide variants (SNVs), in glutamatergic synaptic genes are enriched in schizophrenia patients. However, the majority are too rare to show any association with disease and have not been examined functionally. One such SNV, KALRN-P2255T, displays a penetrance that greatly exceeds that of previously identified schizophrenia-associated SNVs. Therefore, we sought to characterize its effects on the function of kalirin (Kal)-9, a dual Ras-related C3 botulinum toxin substrate 1 and Ras homologue gene family, member A (RhoA) guanine nucleotide exchange factor, upregulated in human schizophrenia brain tissue.
methodsKal9 was overexpressed in primary rat cortical neurons or human embryonic kidney 293 (HEK293) cells. The effects of the P2255T variant on dendritic branching, dendritic spine morphology, protein and messenger RNA stability, and catalytic activity were examined.
resultsKal9-P2255T leads to diminished basal dendritic branching and dendritic spine size, compared with wild-type Kal9. The P2255T SNV directly affected Kal9 protein function, causing increased RhoA activation in HEK293 cells, but had no effect on Ras-related C3 botulinum toxin substrate 1 activation. Consistent with human postmortem findings, we found that Kal9-P2255T protein levels were higher than those of wild-type Kal9 in neurons. Increased messenger RNA stability was detected in HEK293 cells, indicating that this was the cause of the higher protein levels. When analyzed together, increased intrinsic RhoA guanine nucleotide exchange factor catalytic activity combined with increased messenger RNA expression led to net enhancement of RhoA activation, known to negatively impact neuronal morphology.
conclusionsTaken together, our data reveal a novel mechanism for disease-associated SNVs and provide a platform for modeling morphological changes in mental disorders.
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