Splicing of human chloride channel 1

Nakamura, Takumi; Ohsawa-Yoshida, Natsumi; Zhao, Yimeng; Koebis, Michinori; Oana, Kosuke; Mitsuhashi, Hiroaki; Ishiura, Shoichi

doi:10.1016/j.bbrep.2015.11.006

Cited by 3 publications

(4 citation statements)

References 22 publications

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“…One of the main targets affected by the dysregulated CELF1 is a muscle-specific chloride channel ( CLCN1 ). The splicing pattern of this gene has been deeply characterized by Nakamura et al who revealed that CLCN1 expression is driven via AS by CELF1 among other splicing factors and presents a splice variant carrying a PTC [ 156 ]. The CELF1 gain of function reported in DM induces a switch in the CLCN1 splicing pattern towards a higher fraction of AS RNAs containing a PTC, which deeply downregulates its protein expression [ 157 , 158 ].…”

Section: As-nmd Dysfunction and Associated Human Diseasesmentioning

confidence: 99%

Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay

García-Moreno

Romão

2020

IJMS

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Alternative splicing (AS) of precursor mRNA (pre-mRNA) is a cellular post-transcriptional process that generates protein isoform diversity. Nonsense-mediated RNA decay (NMD) is an mRNA surveillance pathway that recognizes and selectively degrades transcripts containing premature translation-termination codons (PTCs), thereby preventing the production of truncated proteins. Nevertheless, NMD also fine-tunes the gene expression of physiological mRNAs encoding full-length proteins. Interestingly, around one third of all AS events results in PTC-containing transcripts that undergo NMD. Numerous studies have reported a coordinated action between AS and NMD, in order to regulate the expression of several genes, especially those coding for RNA-binding proteins (RBPs). This coupling of AS to NMD (AS-NMD) is considered a gene expression tool that controls the ratio of productive to unproductive mRNA isoforms, ultimately degrading PTC-containing non-functional mRNAs. In this review, we focus on the mechanisms underlying AS-NMD, and how this regulatory process is able to control the homeostatic expression of numerous RBPs, including splicing factors, through auto- and cross-regulatory feedback loops. Furthermore, we discuss the importance of AS-NMD in the regulation of biological processes, such as cell differentiation. Finally, we analyze interesting recent data on the relevance of AS-NMD to human health, covering its potential roles in cancer and other disorders.

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Section: As-nmd Dysfunction and Associated Human Diseasesmentioning

confidence: 99%

Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay

García-Moreno

Romão

2020

IJMS

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“…In this study, we sequenced all coding regions of ATP2A2 in a newly identified patient with DD and BD, and identified a previously reported rare mutation, c.1288‐6A>G, near the splice acceptor site of exon 11 (NM_170665). Furthermore, we investigated the effect of c.1288‐6A>G on splicing, using a minigene splicing assay system . Finally, we performed a literature survey and found a significant enrichment of likely gene‐disrupting mutations among the ATP2A2 mutations found in patients with DD with comorbidity of psychoses.…”

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confidence: 99%

Loss of function mutations in ATP2A2 and psychoses: A case report and literature survey

Nakamura

Kazuno

Nakajima

et al. 2016

Psychiatry Clin Neurosci

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Aim: Though genetic factors play a major role in the pathophysiology of psychoses including bipolar disorder (BD) and schizophrenia, lack of wellestablished causative genetic mutations hampers their neurobiological studies. Darier's disease, an autosomal dominant skin disorder caused by mutations of ATP2A2 on chromosome 12q23-24.1, encoding sarco/endoplasmic reticulum calcium transporting ATPase 2 (SERCA2), reportedly cosegregates with BD. A recent genome-wide association study showed an association of schizophrenia with ATP2A2. Methods:We sequenced all coding regions of ATP2A2 in a newly identified patient with Darier's disease and BD. In addition, we performed a literature survey to examine whether likely gene disrupting (LGD) mutations are related to psychoses.Results: We identified a rare heterozygous mutation, c.1288-6A>G, at the 3 0 end of intron 10 in the patient. A minigene splicing assay showed that this mutation introduces a new splice site causing a frameshift and premature stop codon. A literature survey of case reports of patients with Darier's disease and psychoses revealed that the rate of LGD mutations causing frameshift, altered splicing, gain of stop codon, or loss of start codon was significantly higher among the mutations harbored by these cases (9 of 11) than that of ATP2A2 mutations for which comorbidity of psychosis was not reported (107 of 237, P = 0.026). The only non-LGD mutation (p.C560R) reported in patients with Darier's disease and BD caused decreased ATP2A2 protein expression. Conclusion:These results suggest that psychoses in Darier's disease may be caused by a pleiotropic effect of loss-of-function mutations of ATP2A2.

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“…To date, only individual proteins and protein complexes have been investigated in the context of DM1 disease (Forner et al, 2010;Furling et al, 2003;Nakamura et al, 2016), and therefore, there is a notable gap in our understanding of global protein changes in this pathological condition. Although the genetic cause of DM1 is known, a better understanding of the molecular disease processes in animal and human model systems is urgently needed to make progress towards a cure.…”

Section: Introductionmentioning

confidence: 99%

“…To date, mostly only isolated individual proteins and protein complexes have been investigated in the context of DM1 disease (Furling et al, 2003; Forner et al, 2010; Hernández-Hernández et al, 2013; Nakamura et al, 2016) with some exceptions specifically focused on the global proteome changes in neurological context (Sicot et al, 2017; González-Barriga et al, 2021). This leaves a notable gap in our understanding of protein and specifically protein isoform changes in this pathological condition.…”

Section: Introductionmentioning

confidence: 99%

Integrative proteogenomics for differential expression and splicing variation in a DM1 mouse model

Solovyeva

Utzinger²,

Vissières³

et al. 2021

Preprint

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Dysregulated mRNA splicing is involved in the pathogenesis of many diseases including cancer, neurodegenerative diseases, and muscular dystrophies such as myotonic dystrophy type 1 (DM1). Comprehensive assessment of dysregulated splicing on the transcriptome and proteome level have been methodologically challenging, and thus investigations have often been targeting only few genes. Here, we performed a large-scale coordinated transcriptomic and proteomic analysis to characterize a DM1 mouse model (HSALR) in comparison to wild-type. Our integrative proteogenomics approach comprised gene- and splicing-level assessments for mRNAs and proteins. It recapitulated many known instances of aberrant mRNA splicing in DM1 and identified new ones. It enabled the design and targeting of splicing-specific peptides and confirmed the translation of known instances of aberrantly spliced disease-related genes (e.g. Atp2a1, Bin1, Ryr1), complemented by novel findings (e.g. Ywhae, Flnc, Svil). Comparative analysis of large-scale mRNA and protein expression data showed remarkable agreement of differential patterns between disease and wild-type on both the gene and especially the splicing level. We hence believe that our work is suitable as a model for a robust and scalable integrative proteogenomic strategy. This strategy provides investigative approaches, advances our understanding of the disease biology of splicing-based disorders, and helps establish robust splicing-specific biomarkers.

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Splicing of human chloride channel 1

Cited by 3 publications

References 22 publications

Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay

Perspective in Alternative Splicing Coupled to Nonsense-Mediated mRNA Decay

Loss of function mutations in ATP2A2 and psychoses: A case report and literature survey

Integrative proteogenomics for differential expression and splicing variation in a DM1 mouse model

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