Functional analysis of nonsynonymous single nucleotide polymorphisms in human SLC26A9.
Functional analysis of nonsynonymous single nucleotide polymorphisms in human SLC26A9.
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DOI：
10.1002/humu.22107
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发表时间：
2012-08
期刊：
影响因子：
3.9
通讯作者：
Romero, Michael F.
中科院分区：
文献类型：
--
作者：
Chen, An-Ping;Chang, Min-Hwang;Romero, Michael F.
SLC26阴离子转运体在跨上皮细胞对氯离子−的吸收和HCO3−的分泌中起着至关重要的作用；SLC26蛋白突变可导致多种疾病。SLC26a9可作为氯离子−通道和生电氯离子−-HCO3−交换器，并可与cftr相互作用。SLC26A9(−/−)小鼠胃酸分泌减少，但目前没有人类疾病与SLC26A9编码突变有关。因此，我们检测了SLC26A9的非同义编码单核苷酸多态(CSNPs)的功能。目前，NCBI记录了8个cSNP：Y70N、T127N、I384T、R575W、P606L、V622L、V744M和H748R。使用双电极电压钳和阴离子选择电极，我们测量了这些cSNPs的生物物理后果。Y70N(细胞质N-末端)表现出较高的通道活性和增强的氯离子−-HCO3−交换。T127N(跨膜)导致较小的卤化物电流，但对SCN−没有影响。V622L(STAS结构域)和V744M(STAS相邻)减少质膜表达，这是全细胞电流降低的部分原因。然而，V622L的运输量减少到了~50%。SLC26A9基因多态性导致多种功能改变(活性增加、活性降低、蛋白表达改变)，从而可能导致一系列的病理生理过程。因此，了解个体的SLC26A9基因对于了解SLC26A9突变可能引起的疾病或修饰性疾病，如囊性纤维化变得重要。我们的结果也为理解SLC26A9的运输方式和结构-功能关系提供了一个框架。
Slc26 anion transporters play crucial roles in transepithelial Cl− absorption and HCO3− secretion; Slc26 protein mutations lead to several diseases. Slc26a9 functions as a Cl− channel and electrogenic Cl−-HCO3− exchanger, and can interact with CFTR. Slc26a9(−/−) mice have reduced gastric acid secretion, yet no human disease is currently associated with SLC26A9 coding mutations. Therefore, we tested the function of non-synonymous, coding, single nucleotide polymorphisms (cSNPs) of SLC26A9. Presently, eight cSNPs are NCBI-documented: Y70N, T127N, I384T, R575W, P606L, V622L, V744M and H748R. Using two-electrode voltage-clamp and anion selective electrodes, we measured the biophysical consequences of these cSNPs. Y70N (cytoplasmic N-terminus) displays higher channel activity and enhanced Cl−-HCO3− exchange. T127N (transmembrane) results in smaller halide currents but not for SCN−. V622L (STAS domain) and V744M (STAS adjacent) decreased plasma membrane expression which partially accounts for decreased whole cell currents. Nevertheless, V622L transport is reduced to ~50%. SLC26A9 polymorphisms lead to several function modifications (increased activity, decreased activity, altered protein expression) which could lead to a spectrum of pathophysiologies. Thus, knowing an individual’s SLC26A9 genetics becomes important for understanding disease potentially caused by SLC26A9 mutations or modifying diseases, e.g., cystic fibrosis. Our results also provide a framework to understand SLC26A9 transport modalities and structure-function relationships.
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DOI：
10.1085/jgp.200810097
发表时间：
2009-04
期刊：
The Journal of general physiology
影响因子：
--
作者：
Bertrand CA;Zhang R;Pilewski JM;Frizzell RA
通讯作者：
Frizzell RA
DOI：
10.1016/j.biocel.2008.05.007
发表时间：
2008-01-01
影响因子：
4
作者：
Leves, Fiona P.;Tierney, M. Louise;Howitt, Susan M.
通讯作者：
Howitt, Susan M.
影响因子：
5.8
作者：
Larkin, M. A.;Blackshields, G.;Higgins, D. G.
通讯作者：
Higgins, D. G.
影响因子：
4.8
作者：
Kim, KH;Shcheynikov, N;Muallem, S
通讯作者：
Muallem, S
影响因子：
4.8
作者：
Chang, Min-Hwang;Plata, Consuelo;Romero, Michael F.
通讯作者：
Romero, Michael F.