Significant association between <scp>RGS</scp>14 rs12654812 and nephrolithiasis risk among Guangxi population in China

Long, Jun; Chen, Yang; Lin, Haisong; Liao, Ming; Li, Tianyu; Tong, Lei; Wei, Suchun; Xian, Xiaoying; Zhu, Jia; Chen, Jianxin; Tian, Jiarong; Wang, Qiuyan; Mo, Zengnan

doi:10.1002/jcla.22435

Cited by 8 publications

(10 citation statements)

References 22 publications

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“…We determined the effects of identified human genetic variants within the PDZ motif of RGS14 on NHERF1 binding, and found that one (Asp 563 Asn) disrupted the RGS14:NHERF1 complex and blocked RGS14 actions. RGS14 is implicated by numerous GWAS studies to be involved in various forms of chronic kidney diseases (14)(15)(16)(17)(18)(19). Relevant to that, we identified here at least one human genetic variant that blocks RGS14 actions on PTH-sensitive phosphate uptake.…”

Section: Discussionsupporting

confidence: 57%

“…The RGS14 PDZ ligand is present throughout the primate order and in sheep. RGS14 has been implicated by numerous GWAS studies in various forms of chronic human kidney diseases (14)(15)(16)(17)(18)(19). Relevant to that, we identify here one human genetic variant (D563N) that disrupts RGS14 binding to NHERF1 and its capacity to inhibit PTH-sensitive phosphate uptake.…”

Section: Discussionmentioning

confidence: 62%

“…However, human/primate RGS14 differ from the rodent protein in that they also contain a C-terminal Class I PDZ-recognition sequence. Numerous genomewide association studies have implicated RGS14 in kidney diseases (14)(15)(16)(17)(18)(19), including disordered phosphate metabolism. The RGS14 gene on human chromosome 5 is adjacent to SLC34A1 that encodes the NPT2A sodiumphosphate cotransporter.…”

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confidence: 99%

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Genetic variants disrupt human RGS₁₄ binding to NHERF₁ and regulation of NPT₂A-mediated phosphate transport

Friedman

Mamonova

Magyar

et al. 2019

Preprint

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RGS14 has been implicated in disordered phosphate metabolism. The human RGS14 gene is adjacent to SLC34A1 that encodes the NPT2A sodium-phosphate cotransporter. Hormone-regulated NPT2A requires the PDZ protein NHERF1 which contains two PDZ domains (PDZ1 and PDZ2). NHERF1 binds the PDZ ligand carboxy tail of NPT2A to regulate phosphate uptake, and this NPT2A:NHERF1 complex is inhibited by parathyroid hormone (PTH). Studies here define roles for RGS14 in NHERF1-dependent, PTH-sensitive phosphate transport. We found that RGS14 binds to NHERF1 via the PDZ2 domain. PTH inhibits NPT2A-mediated phosphate transport and RGS14 blocked this action. Several rare human mutations have been reported in the RGS14 PDZ ligand located at residues 563 (D563N, D563G) and 565 (A565S, A565V). D563N disrupted RGS14 binding to NHERF1 and did not interfere with PTH action, whereas D563G, A565S, and A565V bound NHERF1 and were functionally equivalent to wild-type RGS14. Computational analysis and molecular dynamics modeling of NHERF1 PDZ2 binding to the RGS14 C-terminal PDZ ligands refined the structural determinants of this interaction. Additional studies demonstrated that RGS14 is expressed in human kidney proximal and distal tubule cells. Together, our findings are consistent with the view that RGS14 contributes to PTH-sensitive phosphate transport in humans. RGS14 coding variants may cause disordered phosphate metabolism.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

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Genetic variants disrupt human RGS₁₄ binding to NHERF₁ and regulation of NPT₂A-mediated phosphate transport

Friedman

Mamonova

Magyar

et al. 2019

Preprint

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“…Recent genomewide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) within the RGS14 gene locus associated with kidney dysfunction [33][34][35]. Subjects with genetic polymorphisms within and outside the RGS14 gene locus have higher susceptibility to nephrolithiasis [34][35][36][37][38], reduced glomerular filtration rates [33], and elevated levels of serum phosphate [39], all of which are indicative of kidney dysfunction [40]. Additionally, SNPs within the RGS14 gene are associated with elevated levels of parathyroid hormone (PTH) [41] and fibroblast growth factor 23 (FGF23) [42], which are both critical for proper kidney function [43].…”

Section: Rgs14 Protein Tissue Distributionmentioning

confidence: 99%

RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain

Harbin

Bramlett

Montañez-Miranda

et al. 2021

IJMS

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The regulator of G-protein signaling 14 (RGS14) is a multifunctional signaling protein that regulates post synaptic plasticity in neurons. RGS14 is expressed in the brain regions essential for learning, memory, emotion, and stimulus-induced behaviors, including the basal ganglia, limbic system, and cortex. Behaviorally, RGS14 regulates spatial and object memory, female-specific responses to cued fear conditioning, and environmental- and psychostimulant-induced locomotion. At the cellular level, RGS14 acts as a scaffolding protein that integrates G protein, Ras/ERK, and calcium/calmodulin signaling pathways essential for spine plasticity and cell signaling, allowing RGS14 to naturally suppress long-term potentiation (LTP) and structural plasticity in hippocampal area CA2 pyramidal cells. Recent proteomics findings indicate that RGS14 also engages the actomyosin system in the brain, perhaps to impact spine morphogenesis. Of note, RGS14 is also a nucleocytoplasmic shuttling protein, where its role in the nucleus remains uncertain. Balanced nuclear import/export and dendritic spine localization are likely essential for RGS14 neuronal functions as a regulator of synaptic plasticity. Supporting this idea, human genetic variants disrupting RGS14 localization also disrupt RGS14’s effects on plasticity. This review will focus on the known and unexplored roles of RGS14 in cell signaling, physiology, disease and behavior.

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“…Association of rs12654812 with nephrolithiasis was validated in a Japanese population 36 . However, studies in Chinese population were not totally consistence with each other 37,38 . RGS14 encodes a member of the regulators of G-protein.…”

Section: Discussionmentioning

confidence: 99%

The rs1256328 (ALPL) and rs12654812 (RGS14) Polymorphisms are Associated with Susceptibility to Calcium Nephrolithiasis in a Taiwanese population

Chen

Chou

Chu

et al. 2019

Sci Rep

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Nephrolithiasis is a common disease affecting almost all populations, with an increasing prevalence over the past decades. Previous studies revealed several functional polymorphisms associated with the pathogenesis of nephrolithiasis. However, data on Asian populations are limited. In this study, three candidate polymorphisms were selected from previous studies to investigate the correlations with nephrolithiasis in a Taiwanese population. In total, 454 nephrolithiasis patients were recruited from Kaohsiung Medical University Hospital, with SNP frequency for 1513 subjects of general population from the Taiwan Biobank (TWB) as a genotypic reference. Results revealed that subjects with minor TT genotype at rs1256328 (alkaline phosphatase, liver/bone/kidney (ALPL)) have higher susceptibility to nephrolithiasis (odds ratio (OR) = 2.03, p = 0.0013). In addition, subjects carrying the minor AA genotype at rs12654812 (regulator of G protein signaling 14 (RGS14)) have higher susceptibility to nephrolithiasis (OR = 1.91, p = 0.0017). Among nephrolithiasis patients, subjects with GG at rs7627468 (calcium-sensing receptor (CASR)) have lower pH level in urine (p = 0.0088). Importantly, rs7627468 is associated with the expressions of IQCB1 and EAF2. rs12654812 could influence the expression of RGS14 itself, MXD3, and FGFR4. In summary, this study successfully validated the genetic roles of rs1256328 and rs12654812 in human nephrolithiasis.

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Significant association between RGS14 rs12654812 and nephrolithiasis risk among Guangxi population in China

Abstract: Our results suggest that the RGS14 polymorphism is involved in the etiology of nephrolithiasis and thus may be a genetic marker for nephrolithiasis.

Cited by 8 publications

References 22 publications

Genetic variants disrupt human RGS₁₄ binding to NHERF₁ and regulation of NPT₂A-mediated phosphate transport

Genetic variants disrupt human RGS₁₄ binding to NHERF₁ and regulation of NPT₂A-mediated phosphate transport

RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain

The rs1256328 (ALPL) and rs12654812 (RGS14) Polymorphisms are Associated with Susceptibility to Calcium Nephrolithiasis in a Taiwanese population

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Significant association between RGS14 rs12654812 and nephrolithiasis risk among Guangxi population in China

Abstract: Our results suggest that the RGS14 polymorphism is involved in the etiology of nephrolithiasis and thus may be a genetic marker for nephrolithiasis.

Cited by 8 publications

References 22 publications

Genetic variants disrupt human RGS14 binding to NHERF1 and regulation of NPT2A-mediated phosphate transport

Genetic variants disrupt human RGS14 binding to NHERF1 and regulation of NPT2A-mediated phosphate transport

RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain

The rs1256328 (ALPL) and rs12654812 (RGS14) Polymorphisms are Associated with Susceptibility to Calcium Nephrolithiasis in a Taiwanese population

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Genetic variants disrupt human RGS₁₄ binding to NHERF₁ and regulation of NPT₂A-mediated phosphate transport

Genetic variants disrupt human RGS₁₄ binding to NHERF₁ and regulation of NPT₂A-mediated phosphate transport