Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway

Wang, Shan; Rhijn, Jon-Ruben van; Akkouh, Ibrahim; Kogo, Naoki; Maas, Nadine; Bleeck, Anna; Ortiz, Irene Santisteban; Lewerissa, Elly; Wu, Kui; Schoenmaker, Chantal; Djurovic, Srdjan; Bokhoven, Hans van; Kleefstra, Tjitske; Kasri, Nael Nadif; Schubert, Dirk W.

doi:10.1016/j.celrep.2022.110790

Cited by 34 publications

(41 citation statements)

References 82 publications

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“…Specifically, the authors found that heterozygous mutations in the histone methyltransferase SET domain-containing protein 1 A ( SETD1A ) led to transcriptional and signaling signatures supporting hyperactivation of the cAMP pathway through upregulation of adenylyl cyclases and downregulation of PDEs. 60 This in turn resulted in increased dendritic branching and length and altered network activity in human iPSC-derived glutamatergic neurons. 60 Therefore, the cAMP/PKA pathway appears to be a common point of convergence downstream of different risk factors for neuropsychiatric disorders and could present a therapeutic target in certain genetic contexts.…”

Section: Discussionmentioning

confidence: 99%

“…60 This in turn resulted in increased dendritic branching and length and altered network activity in human iPSC-derived glutamatergic neurons. 60 Therefore, the cAMP/PKA pathway appears to be a common point of convergence downstream of different risk factors for neuropsychiatric disorders and could present a therapeutic target in certain genetic contexts.…”

Section: Discussionmentioning

confidence: 99%

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The psychosis risk factorRBM12encodes a novel repressor of GPCR/cAMP signal transduction

Semesta

Garces

Tsvetanova

2023

Preprint

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RBM12 is a high-penetrance risk factor for familial schizophrenia and psychosis, yet its precise cellular functions and the pathways to which it belongs are not known. We utilize two complementary models, HEK293 cells and human iPSC-derived neurons, and delineate RBM12 as a novel repressor of the G protein-coupled receptor/cyclic AMP/protein kinase A (GPCR/cAMP/PKA) signaling axis. We establish that loss of RBM12 leads to hyperactive cAMP production and increased PKA activity as well as altered neuronal transcriptional responses to GPCR stimulation. Notably, the cAMP and transcriptional signaling steps are subject to discrete RBM12-dependent regulation. We further demonstrate that the two RBM12 truncating variants linked to familial psychosis impact this interplay, as the mutants fail to rescue GPCR/cAMP signaling hyperactivity in cells depleted of RBM12. Lastly, we present a mechanism underlying the impaired signaling phenotypes. In agreement with its activity as an RNA-binding protein, loss of RBM12 leads to altered gene expression, including that of multiple effectors of established significance within the receptor pathway. Specifically, the abundance of adenylyl cyclases, phosphodiesterase isoforms, and PKA regulatory and catalytic subunits is impacted by RBM12 depletion. We note that these expression changes are fully consistent with the entire gamut of hyperactive signaling outputs. In summary, the current study identifies a previously unappreciated role for RBM12 in the context of the GPCR/cAMP pathway that could be explored further as a tentative molecular mechanism underlying the functions of this factor in neuronal physiology and pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The psychosis risk factorRBM12encodes a novel repressor of GPCR/cAMP signal transduction

Semesta

Garces

Tsvetanova

2023

Preprint

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“… 1 (C) and (D) were adapted from Wang et al. 2 Scale bar = 2 μm. Synapsin/Homer1: n = 25; VGAT/Gephyrin n = 19.…”

Section: Expected Outcomesmentioning

confidence: 99%

Generation of glutamatergic/GABAergic neuronal co-cultures derived from human induced pluripotent stem cells for characterizing E/I balance in vitro

et al. 2023

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“…Genome-wide screening and analysis of de novo insertion/deletion variant transmission pattern identified KMT2F as a candidate susceptibility gene for schizophrenia ( Takata et al, 2014 ), which was supported by a meta-analysis with 1,077 parent–proband trios ( Singh et al, 2016 ). In human neuronal cultures, a heterozygous LoF variant of KMT2F results in increased dendritic length and complexity, as well as increased neuronal bursting activity ( Wang et al, 2022 ). The altered neuronal morphology and activity may underlie KMT2F -associated schizophrenia.…”

Section: Major Epigenetic Mechanisms Associated With Rdeosmentioning

confidence: 99%

“…Samples from schizophrenia patients show increased microglial activity, accompanied by aberrant synaptic pruning and lowered dendritic spine density ( Glausier and Lewis, 2013 ; Sellgren et al, 2019 ). However, iPSC-derived neurons with KMT2F-associated schizophrenia variants showed increased dendritic length and complexity ( Wang et al, 2022 ). The cellular phenotype resembles that of ASD ( Hutsler and Zhang, 2010 ; Varghese et al, 2017 ; Weir et al, 2018 ), another common disorder that is often caused by altered H3K4 methylation ( Shen et al, 2014 ; Collins et al, 2019 ).…”

Section: Extending the Rdeo Findings To Common Complex Diseasesmentioning

confidence: 99%

Rare diseases of epigenetic origin: Challenges and opportunities

Merrill

Sharma

et al. 2023

Front. Genet.

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Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace of discovery of novel RDs and provided more accurate means for their diagnosis. RDs that are driven by altered epigenetic regulation with an underlying genetic basis are referred to as rare diseases of epigenetic origin (RDEOs). These diseases pose unique challenges in research, as they often show complex genetic and clinical heterogeneity arising from unknown gene–disease mechanisms. Furthermore, multiple other factors, including cell type and developmental time point, can confound attempts to deconvolute the pathophysiology of these disorders. These challenges are further exacerbated by factors that contribute to epigenetic variability and the difficulty of collecting sufficient participant numbers in human studies. However, new molecular and bioinformatics techniques will provide insight into how these disorders manifest over time. This review highlights recent studies addressing these challenges with innovative solutions. Further research will elucidate the mechanisms of action underlying unique RDEOs and facilitate the discovery of treatments and diagnostic biomarkers for screening, thereby improving health trajectories and clinical outcomes of affected patients.

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Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway

Cited by 34 publications

References 82 publications

The psychosis risk factorRBM12encodes a novel repressor of GPCR/cAMP signal transduction

The psychosis risk factorRBM12encodes a novel repressor of GPCR/cAMP signal transduction

Generation of glutamatergic/GABAergic neuronal co-cultures derived from human induced pluripotent stem cells for characterizing E/I balance in vitro

Rare diseases of epigenetic origin: Challenges and opportunities

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