Regulation of TRPV1 by a novel renally expressed rat TRPV1 splice variant

2006 ◽  
Vol 290 (1) ◽  
pp. F117-F126 ◽  
Author(s):  
Wei Tian ◽  
Yi Fu ◽  
Donna H. Wang ◽  
David M. Cohen
Keyword(s):  
Splice Variant ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Splice Variants ◽  
Stop Codon ◽  
Rat Kidney ◽  
Dominant Negative ◽  
Epithelial Cell Line ◽  
Hek 293 ◽  
Donor And Acceptor

The capsaicin receptor and transient receptor potential channel TRPV1 senses heat, protons, and vanilloid agonists in peripheral sensory ganglia. Abundant data have suggested the presence of potentially novel splice variants in the kidney. We report a novel rat TRPV1 splice variant, TRPV1VAR, cloned from kidney papilla. TRPV1VAR cDNA was identified in multiple kidney tissues. Its sequence was fully compatible with potential splice donor and acceptor sites in the rat TRPV1 gene. TRPV1VAR is predicted to encode a truncated form of TRPV1 consisting of the NH2-terminal 248 residues of TRPV1 (all within the NH2-terminal intracellular domain) followed by five nonconsensus amino acids (Arg-Glu-Ala-Met-Trp) and a stop codon. The variant utilizes the same consensus Kozak sequence as canonical TRPV1. A band of the appropriate molecular mass was identified in rat kidney papillary (but not medullary) lysates immunoblotted with an antibody directed against the NH2 terminus of TRPV1, whereas an antibody recognizing the TRPV1 COOH terminus failed to detect it. Upon heterologous expression in HEK 293 cells, TRPV1VAR potentiated the ability of cotransfected TRPV1 to confer calcium influx in response to resiniferatoxin. TRPV1VAR did not influence expression or cell surface localization of cotransfected TRPV1. TRPV1VAR protein product associated with the NH2 terminus of canonical TRPV1. Interestingly, when expressed in the COS-7 epithelial cell line, TRPV1VAR functioned in a dominant-negative acting capacity, partially blocking TRPV1-dependent resiniferatoxin responsiveness. We conclude that TRPV1VAR is one of perhaps several TRPV1 splice variants expressed in rat kidney and that it may serve to modulate TRPV1 responsiveness in some tissues.

scholarly journals An Alternative Splice Variant of HIPK2 with Intron Retention Contributes to Cytokinesis

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 484 ◽  
Author(s):  
Veronica Gatti ◽  
Manuela Ferrara ◽  
Ilaria Virdia ◽  
Silvia Matteoni ◽  
Laura Monteonofrio ◽  
...  
Keyword(s):  
Cell Division ◽  
Stress Response ◽  
Alternative Splice ◽  
Functional Activity ◽  
Splice Variant ◽  
Splice Variants ◽  
Stop Codon ◽  
Cellular Stress Response ◽  
Dependent Manner ◽  
Western Blots

HIPK2 is a DYRK-like kinase involved in cellular stress response pathways, development, and cell division. Two alternative splice variants of HIPK2, HIPK2-FL and HIPK2-Δe8, have been previously identified as having different protein stability but similar functional activity in the stress response. Here, we describe one additional HIPK2 splice variant with a distinct subcellular distribution and functional activity in cytokinesis. This novel splice variant lacks the last two exons and retains intron13 with a stop codon after 89 bp of the intron, generating a short isoform, HIPK2-S, that is detectable by 2D Western blots. RT-PCR analyses of tissue arrays and tumor samples show that HIPK2-FL and HIPK2-S are expressed in normal human tissues in a tissue-dependent manner and differentially expressed in human colorectal and pancreatic cancers. Gain- and loss-of-function experiments showed that in contrast to HIPK2-FL, HIPK2-S has a diffuse, non-speckled distribution and is not involved in the DNA damage response. Rather, we found that HIPK2-S, but not HIPK2-FL, localizes at the intercellular bridge, where it phosphorylates histone H2B and spastin, both required for faithful cell division. Altogether, these data show that distinct human HIPK2 splice variants are involved in distinct HIPK2-regulated functions like stress response and cytokinesis.

scholarly journals Cellular cholesterol controls TRPC3 function: evidence from a novel dominant-negative knockdown strategy

2006 ◽  
Vol 396 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Annarita Graziani ◽  
Christian Rosker ◽  
Sepp D. Kohlwein ◽  
Michael X. Zhu ◽  
Christoph Romanin ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Transient Receptor Potential ◽  
Lipid Membrane ◽  
Membrane Conductance ◽  
Receptor Potential ◽  
Surface Expression ◽  
Dominant Negative ◽  
Membrane Microdomains ◽  
Membrane Expression ◽  
Hek 293

TRPC3 (canonical transient receptor potential protein 3) has been suggested to be a component of cation channel complexes that are targeted to cholesterol-rich lipid membrane microdomains. In the present study, we investigated the potential role of membrane cholesterol as a regulator of cellular TRPC3 conductances. Functional experiments demonstrated that cholesterol loading activates a non-selective cation conductance and a Ca2+ entry pathway in TRPC3-overexpressing cells but not in wild-type HEK-293 (human embryonic kidney 293) cells. The cholesterol-induced membrane conductance exhibited a current-to-voltage relationship similar to that observed upon PLC (phospholipase C)-dependent activation of TRPC3 channels. Nonetheless, the cholesterol-activated conductance lacked negative modulation by extracellular Ca2+, a typical feature of agonist-activated TRPC3 currents. Involvement of TRPC3 in the cholesterol-dependent membrane conductance was further corroborated by a novel dominant-negative strategy for selective blockade of TRPC3 channel activity. Expression of a TRPC3 mutant, which contained a haemagglutinin epitope tag in the second extracellular loop, conferred antibody sensitivity to both the classical PLC-activated as well as the cholesterol-activated conductance in TRPC3-expressing cells. Moreover, cholesterol loading as well as PLC stimulation was found to increase surface expression of TRPC3. Promotion of TRPC3 membrane expression by cholesterol was persistent over 30 min, while PLC-mediated enhancement of plasma membrane expression of TRPC3 was transient in nature. We suggest the cholesterol content of the plasma membrane as a determinant of cellular TRPC3 activity and provide evidence for cholesterol dependence of TRPC3 surface expression.

Cells expressing unique Na+/Ca2+ exchange (NCX1) splice variants exhibit different susceptibilities to Ca2+ overload

2006 ◽  
Vol 290 (5) ◽  
pp. H2155-H2162 ◽  
Author(s):  
Cecilia Hurtado ◽  
Michele Prociuk ◽  
Thane G. Maddaford ◽  
Elena Dibrov ◽  
Nasrin Mesaeli ◽  
...  
Keyword(s):  
Splice Variant ◽  
Cardiac Glycosides ◽  
Splice Variants ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
Neonatal Cardiomyocytes ◽  
Simulated Ischemia ◽  
293 Cells ◽  
Intracellular Ca ◽  
Specific Alternative

The Na+/Ca2+ exchanger (NCX) NCX1 exhibits tissue-specific alternative splicing. Such NCX splice variants as NCX1.1 and NCX1.3 are also differentially regulated by Na+ and Ca2+, although the physiological implications of these regulatory characteristics are unclear. On the basis of their distinct regulatory profiles, we hypothesized that cells expressing these different splice variants might exhibit unique responses to conditions promoting Ca2+ overload, such as during exposure to cardiac glycosides or simulated ischemia. NCX1.1 or NCX1.3 was expressed in human embryonic kidney (HEK)-293 cells or rat neonatal ventricular cardiomyocytes (NVC), and expression was confirmed by Western blotting and immunocytochemical analyses. HEK-293 cells lacked NCX1 protein before transfection. With use of adenoviral vectors, neonatal cardiomyocytes were induced to overexpress the NCX1.1 splice variant by nearly twofold, whereas the NCX1.3 isoform was expressed on the endogenous NCX1.1 background. Total expression was comparable for NCX1.1 and NCX1.3. Exposure of NVC to ouabain induced a significant increase in cellular Ca2+, an effect that was exaggerated in cells overexpressing NCX1.1, but not NCX1.3. The increase in intracellular Ca2+ was inhibited by 5 μM KB-R7943. Cardiomyocytes overexpressing NCX1.1 also exhibited a greater accumulation of intracellular Ca2+ in response to simulated ischemia than did cells expressing NCX1.3. Similar responses were observed in HEK-293 cells where NCX1.1 was expressed. We conclude that expression of the NCX1.3 splice variant protects against severe Ca2+ overload, whereas NCX1.1 promotes Ca2+ overload in response to cardiac glycosides and ischemic challenges. These results highlight the importance of ionic regulation in controlling NCX1 activity under conditions that promote Ca2+ overload.

Cloning, expression and subcellular localization of two novel splice variants of mouse transient receptor potential channel 2

2000 ◽  
Vol 351 (1) ◽  
pp. 115-122 ◽  
Author(s):  
Thomas HOFMANN ◽  
Michael SCHAEFER ◽  
Günter SCHULTZ ◽  
Thomas GUDERMANN
Keyword(s):  
Membrane Trafficking ◽  
Fusion Proteins ◽  
Transient Receptor Potential ◽  
Splice Variants ◽  
Receptor Potential ◽  
Calcium Entry ◽  
Transient Receptor Potential Channels ◽  
Protein Fusion ◽  
Hek 293 ◽  
Transient Receptor

Transient receptor potential channels (TRPCs) are known as candidate molecular correlates of receptor-activated or store-operated calcium entry. While functional roles for most TRPCs have been suggested, the physiological relevance of TRPC2 remains obscure. Whereas human and bovine TRPC2 are candidate pseudogenes, full-length rodent TRPC2 transcripts have been reported. There is, however, considerable controversy concerning mRNA splicing, tissue distribution and the function of these proteins. We report the molecular cloning of two novel murine TRPC2 splice variants, mTRPC2α and mTRPC2β. mTRPC2α RNA is expressed at low levels in many tissues and cell systems, while mTRPC2β is exclusively and abundantly expressed in the vomeronasal organ (VNO). When expressed in human embryonic kidney (HEK)-293 cells, mTRPC2 did not enhance receptor- or store-activated calcium entry. In order to investigate the basis of such a functional defect, mTRPC2–green fluorescent protein fusion proteins were examined by confocal microscopy. Fusion proteins were retained in endomembranes when expressed in HEK-293 or other cells of epithelial or neuronal origin. Co-expression of TRPC2 with other TRPCs did not restore plasma-membrane trafficking. We conclude that TRPC2 may form functional channels in the cellular context of the VNO, but is unlikely to have a physiological function in other tissues. The sequences of mTRPC2α and mTRPC2β have been submitted to GenBank under the accession numbers AF230802 and AF230803 respectively.

scholarly journals Functional diversity of PFKFB3 splice variants in glioblastomas

2020 ◽  
Author(s):  
Ulli Heydasch ◽  
Renate Kessler ◽  
Jan-Peter Warnke ◽  
Klaus Eschrich ◽  
Nicole Scholz ◽  
...  
Keyword(s):  
Splice Variant ◽  
Splice Variants ◽  
Aerobic Glycolysis ◽  
Diagnostic Value ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
Specific Effects ◽  
293 Cells ◽  
Common Notion ◽  
The Impact

AbstractTumor cells tend to metabolize glucose through aerobic glycolysis instead of oxidative phosphorylation in mitochondria. One of the rate limiting enzymes of glycolysis is 6-phosphofructo-1-kinase, which is allosterically activated by fructose 2,6-bisphosphate which in turn is produced by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2 or PFKFB). Mounting evidence suggests that cancerous tissues overexpress the PFKFB isoenzyme, PFKFB3, being causing enhanced proliferation of cancer cells.Initially, six PFKFB3 splice variants with different C-termini have been documented in humans. More recently, additional splice variants with varying N-termini were discovered the functions of which are to be uncovered.Glioblastoma is one of the deadliest forms of brain tumors. Up to now, the role of PFKFB3 splice variants in the progression and prognosis of glioblastomas is only partially understood. In this study, we first re-categorized the PFKFB3 splice variant repertoire to simplify the denomination. We investigated the impact of increased and decreased levels of PFKFB3-4 (former UBI2K4) and PFKFB3-5 (former variant 5) on the viability and proliferation rate of glioblastoma U87 and HEK-293 cells. The simultaneous knock-down of PFKFB3-4 and PFKFB3-5 led to a decrease in viability and proliferation of U87 and HEK-293 cells as well as a reduction in HEK-293 cell colony formation. Overexpression of PFKFB3-4 but not PFKFB3-5 resulted in increased cell viability and proliferation. This finding contrasts with the common notion that overexpression of PFKFB3 enhances tumor growth, but instead suggests splice variant-specific effects of PFKFB3, apparently with opposing effects on cell behaviour. Strikingly, in line with this result, we found that in human IDH-wildtype glioblastomas, the PFKFB3-4 to PFKFB3-5 ratio was significantly shifted towards PFKFB3-4 when compared to control brain samples. Our findings indicate that the expression level of distinct PFKFB3 splice variants impinges on tumorigenic properties of glioblastomas and that splice pattern may be of important diagnostic value for glioblastoma.

scholarly journals Splice variants’ role in mediating different disease states in tissue requiring ion transduction through calcium channel for function

2017 ◽  
Author(s):  
Wenfa Ng
Keyword(s):  
Alternative Splicing ◽  
Calcium Channel ◽  
Alternative Splice ◽  
Splice Variant ◽  
Splice Variants ◽  
Energetic Cost ◽  
Hypoxic Stress ◽  
Tissue Samples ◽  
Hek 293 ◽  
Selection Of

Structure informs function, and this may be the evolutionary reason why alternative splicing, which is capable of generating different variants of the same protein, arise. But, given the energetic cost of generating different splice variants for testing their capability at a specific task, which incurs cellular functional uncertainty; as well as the exertion of differing physiological effects on cells that may translate into diseased states, what is the evolutionary advantage of this process? Additionally, what are the factors that select a specific variant for a presented task? Using heart tissue samples exposed to hypoxia stress as model system, this research idea entails the illumination of single nucleotide polymorphisms (SNP) of the calcium channel transporter, Cav 1.2 gene in the population through gene sequencing followed by bioinformatic analysis for alternative splice sites. This would be followed by a scan for alternative splice variants through colony polymerase chain reaction using universal primers for Cav 1.2 gene. Confirmation of splice variant identity through Western blot laid the stage for subsequent efforts at cloning and expressing the variant gene in HEK 293 cells lacking endogenous expression of Cav 1.2, for biophysical characterization of calcium conduction through patch clamp electrophysiology. In parallel, structural elucidation efforts necessitate the purification of the calcium channel via hydrophobic interaction or reversed phase liquid chromatography after its heterologous expression in a bacterial host. But, biophysical and biochemical characterization does not speak of the signaling and metabolic pathways laying the path to generation of the splice variant(s). Hence, discovery approaches such as RNA-seq and mass spectrometry proteomics could uncover the molecular mysteries at the transcript and protein level that help guide the selection of specific splice variant in response to hypoxic stress, where HIF is a candidate pathway. Implementing this approach from the retrospective angle of examining diseased human tissue samples provide one important facet for uncovering possible mechanisms driving the generation of a splice variant. However, the complementary prospective approach of identifying the molecular basis and processes for responding to hypoxia in a cell line such as HEK 293 would help provide confirmatory evidence in understanding the key drivers of physiological response to lack of oxygen at the cellular level. Collectively, this research route would illuminate both the nucleotide informational basis of alternative splicing in calcium channel Cav 1.2 as well as identify the molecular mechanisms enabling the selection of specific splice variants useful for conferring, at the cell and tissue level, ability to withstand hypoxic stress without significant negative effects on cell function. Interested readers can expand on the ideas presented.

scholarly journals Functional diversity of PFKFB3 splice variants in glioblastomas

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0241092
Author(s):  
Ulli Heydasch ◽  
Renate Kessler ◽  
Jan-Peter Warnke ◽  
Klaus Eschrich ◽  
Nicole Scholz ◽  
...  
Keyword(s):  
Splice Variant ◽  
Splice Variants ◽  
Aerobic Glycolysis ◽  
Diagnostic Value ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
Specific Effects ◽  
293 Cells ◽  
Common Notion ◽  
The Impact

Tumor cells tend to metabolize glucose through aerobic glycolysis instead of oxidative phosphorylation in mitochondria. One of the rate limiting enzymes of glycolysis is 6-phosphofructo-1-kinase, which is allosterically activated by fructose 2,6-bisphosphate which in turn is produced by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2 or PFKFB). Mounting evidence suggests that cancerous tissues overexpress the PFKFB isoenzyme, PFKFB3, being causing enhanced proliferation of cancer cells. Initially, six PFKFB3 splice variants with different C-termini have been documented in humans. More recently, additional splice variants with varying N-termini were discovered the functions of which are to be uncovered. Glioblastoma is one of the deadliest forms of brain tumors. Up to now, the role of PFKFB3 splice variants in the progression and prognosis of glioblastomas is only partially understood. In this study, we first re-categorized the PFKFB3 splice variant repertoire to simplify the denomination. We investigated the impact of increased and decreased levels of PFKFB3-4 (former UBI2K4) and PFKFB3-5 (former variant 5) on the viability and proliferation rate of glioblastoma U87 and HEK-293 cells. The simultaneous knock-down of PFKFB3-4 and PFKFB3-5 led to a decrease in viability and proliferation of U87 and HEK-293 cells as well as a reduction in HEK-293 cell colony formation. Overexpression of PFKFB3-4 but not PFKFB3-5 resulted in increased cell viability and proliferation. This finding contrasts with the common notion that overexpression of PFKFB3 enhances tumor growth, but instead suggests splice variant-specific effects of PFKFB3, apparently with opposing effects on cell behaviour. Strikingly, in line with this result, we found that in human IDH-wildtype glioblastomas, the PFKFB3-4 to PFKFB3-5 ratio was significantly shifted towards PFKFB3-4 when compared to control brain samples. Our findings indicate that the expression level of distinct PFKFB3 splice variants impinges on tumorigenic properties of glioblastomas and that splice pattern may be of important diagnostic value for glioblastoma.

scholarly journals Cloning, Expression, and Functional Characterization of Relaxin Receptor (Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 7) Splice Variants from Human Fetal Membranes

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1277-1294 ◽  
Author(s):  
András Kern ◽  
Daniela Hubbard ◽  
Aaron Amano ◽  
Gillian D. Bryant-Greenwood
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
G Protein ◽  
Splice Variant ◽  
Splice Variants ◽  
Dominant Negative ◽  
Fetal Membranes ◽  
Leucine Rich Repeat ◽  
G Protein Coupled ◽  
Relaxin Receptor

The relaxin receptor [leucine-rich repeat-containing G protein-coupled receptor 7 (LGR7)] belongs to the leucine-rich repeat containing G protein-coupled receptors subgroup C. Three new LGR7 splice variants have been cloned from the human fetal membranes and shown to be truncated versions of the full-length receptor, encoded by different lengths of the extracellular domain. The expression of their mRNAs has been confirmed by both qualitative and quantitative PCR and shown to be higher in the chorion and decidua before, compared with after, spontaneous labor. When HEK293 cells were transfected with each LGR7 splice variant, their proteins were retained within the endoplasmic reticulum. However, the protein for the shortest variant was also secreted into the medium. We have characterized the intracellular functions and effects of these LGR7 variants on the function of the wild-type (WT)-LGR7. In coexpression studies, each splice variant interacted directly with the WT-LGR7 and exerted a dominant-negative effect on cAMP accumulation by the WT-LGR7 after relaxin treatment. This interaction resulted in the sequestration of the WT-LGR7 inside the cells by down-regulation of its maturation and cell surface delivery. The constitutive homodimerization of WT-LGR7 has been shown here to take place in the endoplasmic reticulum, and the presence of any one of the splice variants decreased this by the formation of heterodimers with the WT-LGR7, supporting the view that homodimerization is a prerequisite for receptor trafficking to the cell surface. These data suggest that the dominant-negative effects of the LGR7 splice variants expressed in the chorion and decidua could be functionally significant in the peripartal period by inhibiting the function of WT-LGR7 and dampening the responsiveness of these tissues to endogenous relaxin.

Mediation of angiotensin II-induced Ca2+ signaling by polycystin 2 in glomerular mesangial cells

2008 ◽  
Vol 294 (4) ◽  
pp. F909-F918 ◽  
Author(s):  
Juan Du ◽  
Min Ding ◽  
Sherry Sours-Brothers ◽  
Sarabeth Graham ◽  
Rong Ma
Keyword(s):  
Transient Receptor Potential ◽  
Mesangial Cells ◽  
Rat Kidney ◽  
Receptor Potential ◽  
Cell Types ◽  
Protein Product ◽  
Dominant Negative ◽  
Ang Ii ◽  
Glomerular Mesangial Cells ◽  
Autosomal Dominant Polycystic Kidney

Ca+ influx across the plasma membrane is a major component of mesangial cell (MC) response to vasoconstrictors. Polycystin 2 (PC2), the protein product of the gene mutated in type 2 autosomal dominant polycystic kidney disease, has been shown to function as a nonselective cation channel in a variety of cell types. The present study was performed to test the hypothesis that PC2 and its binding partners constitute a Ca2+-permeable channel and contribute to ANG II-induced Ca2+ signaling in MCs. Western blot and immunocytochemistry showed PC2 expression in cultured human MCs. The existence of PC2 in MCs was further confirmed by immunohistochemsitry in rat kidney sections. Coimmunoprecipitation displayed a selective interaction of PC2 with canonical transient receptor potential (TRPC) proteins TRPC1 and TRPC4. Cell-attached patch-clamp experiments revealed that ANG II-induced membrane currents were enhanced by overexpression of pkd2 but significantly inhibited by knock down of pkd2, 30 μM Gd3+ (a PC2 channel blocker), and dominant-negative pkd2 mutant (pkd2-D511V). Corresponding to the increase in channel currents, ANG II stimulation increased expression of PC2 on the cell surface of MCs and interaction with TRPC1 and TRPC4. Furthermore, ANG II-induced MC contraction was significantly reduced in pkd2-knocked down MCs. These data suggest that PC2 selectively assembles with TRPC1 and TRPC4 to form channel complexes mediating ANG II-induced Ca2+ responses in MCs.

scholarly journals Distinct Morphological and Behavioural Alterations in ENU-Induced Heterozygous Trpc7K810Stop Mutant Mice

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1732
Author(s):  
Birgit Rathkolb ◽  
Maike Howaldt ◽  
Stefan Krebs ◽  
Petra Prückl ◽  
Susanne Sauer ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Transient Receptor Potential ◽  
Stop Codon ◽  
Inbred Mice ◽  
Dominant Negative ◽  
Mutant Mice ◽  
Mutant Line ◽  
Dominant Negative Effect ◽  
Causative Mutation ◽  
Phenotypic Characterization

Trpc7 (transient receptor potential cation channel, subfamily C, member 7; 862 amino acids) knockout mice are described showing no clear phenotypic alterations, therefore, the functional relevance of the gene remains unclear. A complementary approach for the functional analysis of a given gene is the examination of individuals harbouring a mutant allele of the gene. In the phenotype-driven Munich ENU mouse mutagenesis project, a high number of phenotypic parameters was used for establishing novel mouse models on the genetic background of C3H inbred mice. The phenotypically dominant mutant line SMA002 was established and further examined. Analysis of the causative mutation as well as the phenotypic characterization of the mutant line were carried out. The causative mutation was detected in the gene Trpc7 which leads to the production of a truncated protein due to the novel stop codon at amino acid position 810 thereby affecting the highly conserved cytoplasmic C terminus of the protein. Trpc7 heterozygous mutant mice of both sexes were viable and fertile, but showed distinct morphological and behavioural alterations which is in contrast to the published phenotype of Trpc7 knockout mice. Thus, the Trpc7K810Stop mutation leads to a dominant negative effect of the mutant protein.

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