PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion.
PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion.
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家族性痉挛性截瘫的PMCA4（ATP2B4）突变会导致细胞内钙挤出延迟。
DOI：
10.1002/brb3.321
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发表时间：
2015-04
影响因子：
3.1
通讯作者：
Ho, Shu-Leong
中科院分区：
文献类型：
--
作者：
Ho, Philip Wing-Lok;Pang, Shirley Yin-Yu;Li, Miaoxin;Tse, Zero Ho-Man;Kung, Michelle Hiu-Wai;Sham, Pak-Chung;Ho, Shu-Leong
家族性痉挛性截瘫（FSP）是一种异质性疾病，主要以进行性下肢痉挛和虚弱为特征。已有50多个疾病位点被描述为具有不同的遗传模式。最近，我们在一个常染色体显性FSP的中国家庭中描述了一种新的质膜钙atp酶（PMCA4或ATP2B4）基因错义突变（c.803G> a, p.R268Q）。在此基础上，我们进一步描述了这种突变的功能影响。当PMCA4去除细胞质钙时，我们使用fura-2荧光染料和共聚焦显微镜观察了过表达野生型或R268Q突变型PMCA4的人SH-SY5Y神经母细胞瘤细胞中细胞质钙水平的瞬时变化和随时间变化的衰减。与载体对照细胞相比，过表达野生型和R268Q PMCA4显著降低了kcl诱导去极化后的最大钙峰值。然而，与野生型相比，过表达突变PMCA4蛋白的细胞表现出明显更高的钙激增水平。此外，在SERCA被thapsigargin抑制后，这些突变细胞的稳态胞质钙浓度仍明显高于野生型。我们的研究结果表明，PMCA4 p.R268Q突变导致人类神经元细胞钙稳态的功能改变。这提示钙的失调可能与FSP的发病机制有关。
Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. Recently, we described a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP. Further to this finding, here we describe the functional effect of this mutation. As PMCA4 removes cytosolic calcium, we measured transient changes and the time-dependent decay of cytosolic calcium level as visualized by using fura-2 fluorescent dye with confocal microscopy in human SH-SY5Y neuroblastoma cells overexpressing either wild-type or R268Q mutant PMCA4. Overexpressing both wild-type and R268Q PMCA4 significantly reduced maximum calcium surge after KCl-induced depolarization as compared with vector control cells. However, cells overexpressing mutant PMCA4 protein demonstrated significantly higher level of calcium surge when compared with wild-type. Furthermore, the steady-state cytosolic calcium concentration in these mutant cells remained markedly higher than the wild-type after SERCA inhibition by thapsigargin. Our result showed that p.R268Q mutation in PMCA4 resulted in functional changes in calcium homeostasis in human neuronal cells. This suggests that calcium dysregulation may be associated with the pathogenesis of FSP.
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影响因子：
13.9
作者：
Blackstone C
通讯作者：
Blackstone C
影响因子：
2.7
作者：
Strehler, Emanuel E.
通讯作者：
Strehler, Emanuel E.
影响因子：
3.7
作者：
Ho, Philip Wing-Lok;Liu, Hui-Fang;Ho, Jessica Wing-Man;Zhang, Wei-Yi;Chu, Andrew Chi-Yuen;Kwok, Ken Hon-Hung;Ge, Xuan;Chan, Koon-Ho;Ramsden, David Boyer;Ho, Shu-Leong
通讯作者：
Ho, Shu-Leong
影响因子：
4.8
作者：
Sepúlveda, MR;Berrocal-Carrillo, MB;Mata, AM
通讯作者：
Mata, AM
DOI：
10.1126/science.1247363
发表时间：
2014-01-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Novarino G;Fenstermaker AG;Zaki MS;Hofree M;Silhavy JL;Heiberg AD;Abdellateef M;Rosti B;Scott E;Mansour L;Masri A;Kayserili H;Al-Aama JY;Abdel-Salam GMH;Karminejad A;Kara M;Kara B;Bozorgmehri B;Ben-Omran T;Mojahedi F;El Din Mahmoud IG;Bouslam N;Bouhouche A;Benomar A;Hanein S;Raymond L;Forlani S;Mascaro M;Selim L;Shehata N;Al-Allawi N;Bindu PS;Azam M;Gunel M;Caglayan A;Bilguvar K;Tolun A;Issa MY;Schroth J;Spencer EG;Rosti RO;Akizu N;Vaux KK;Johansen A;Koh AA;Megahed H;Durr A;Brice A;Stevanin G;Gabriel SB;Ideker T;Gleeson JG
通讯作者：
Gleeson JG