Functional Analysis of Rare Genetic Variants in the Negative Regulator of Intracellular Calcium Signaling RCAS/SLC10A7.
Functional Analysis of Rare Genetic Variants in the Negative Regulator of Intracellular Calcium Signaling RCAS/SLC10A7.
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DOI：
10.3389/fmolb.2021.741946
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发表时间：
2021
影响因子：
5
通讯作者：
Geyer J
中科院分区：
文献类型：
--
作者：
Wannowius M;Karakus E;Geyer J
溶质载体家族10个成员SLC10A7是细胞内钙信号(RCAS)的负调节因子。在细胞培养中，SLC10A7的表达与通过质膜的钙内流(SOCE)呈负相关。在thapsigargin耗尽内质网钙库后，SLC10A7缺陷细胞显著增加了钙内流，而SLC10A7/RCAS过表达则限制了钙内流。人类SLC10A7基因的遗传变异与骨骼发育不良和成釉发育不全有关，并揭示了细胞钙内流功能的丧失。最近，又发现了一个与疾病相关的遗传变异(P303L)以及一些新的遗传变异(V235F、T221M、I136M、L210F、P285L和G146S)。在本研究中，这些突变体在HEK293细胞中表达，以研究它们的亚细胞定位及其对细胞内钙内流的影响。所有的变异体都被正确地分类到内质网隔室，并与SOCE的功能成分STIM蛋白紧密共存。与野生型相比，突变体P303L和L210F对细胞内钙内流的影响显著降低，但仍保持一定程度的残余活性。这可能解释了携带P303L变异的患者的较温和的表型，并可能预示着新发现的L210F变异的潜在疾病。相比之下，所有其他变种的表现与野生型相似。综上所述，骨骼发育不良和成釉发育不全患者应考虑SLC10A7基因变异的发生。除了已经确定的变种外，本研究还发现了另一个潜在的与疾病相关的SLC10A7/RCAS变种，即L210F，它似乎在南亚人群中最常见。
The solute carrier family 10 member SLC10A7 is a negative regulator of intracellular calcium signaling (RCAS). In cell culture, SLC10A7 expression is negatively correlated with store-operated calcium entry (SOCE) via the plasma membrane. SLC10A7-deficient cells have significantly increased calcium influx after treatment with thapsigargin for depletion of ER calcium stores, whereas SLC10A7/RCAS overexpression limits calcium influx. Genetic variants in the human SLC10A7 gene are associated with skeletal dysplasia and amelogenesis imperfecta and reveal loss of function on cellular calcium influx. More recently, an additional disease-related genetic variant (P303L) as well as some novel genetic variants (V235F, T221M, I136M, L210F, P285L, and G146S) have been identified. In the present study, these variants were expressed in HEK293 cells to study their subcellular localization and their effect on cellular calcium influx. All variants were properly sorted to the ER compartment and closely co-localized with the STIM protein, a functional component of SOCE. The variants P303L and L210F showed significantly reduced effects on cellular calcium influx compared to the wild type but still maintained some degree of residual activity. This might explain the milder phenotype of patients bearing the P303L variant and might indicate disease potential for the newly identified L210F variant. In contrast, all other variants behaved like the wild type. In conclusion, the occurrence of variants in the SLC10A7 gene should be considered in patients with skeletal dysplasia and amelogenesis imperfecta. In addition to the already established variants, the present study identifies another potential disease-related SLC10A7/RCAS variant, namely, L210F, which seems to be most frequent in South Asian populations.
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作者：
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通讯作者：
Geyer, Joachim
Stim1，是存储经营的Ca2+通道函数的必不可少的组件。
影响因子：
7.8
作者：
Roos, Jack;DiGregorio, Paul J;Yeromin, Andriy V;Ohlsen, Kari;Lioudyno, Maria;Zhang, Shenyuan;Safrina, Olga;Kozak, J Ashot;Wagner, Steven L;Cahalan, Michael D;Velicelebi, Gonul;Stauderman, Kenneth A
通讯作者：
Stauderman, Kenneth A