The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein
The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein
复制标题
DOI：
10.1182/blood-2008-07-171140
复制
发表时间：
2009-02-05
期刊：
影响因子：
20.3
通讯作者：
Stewart, Gordon W.
中科院分区：
文献类型：
--
作者：
Bruce, Lesley J.;Guizouarn, Helene;Stewart, Gordon W.
过度水合的遗传性口细胞增多症是一种罕见的显性遗传性溶血性贫血，其特征是大量的膜渗漏到单价阳离子。在这里，我们表明，OHSt红细胞膜含有轻微减少量的Rh相关糖蛋白（RhAG），一个假定的气体通道蛋白。DNA分析显示，OHSt患者的RHAG中有2个杂合突变（t182 g，t194 c）中的1个，导致2个高度保守的氨基酸（Ile 61 Arg，Phe 65 Ser）取代。出乎意料的是，野生型RhAG在非洲爪蟾卵母细胞中的表达诱导单价阳离子泄漏;突变体RhAG蛋白的表达诱导的泄漏比野生型大约6倍。RhAG属于形成孔样结构的铵转运蛋白家族。我们已经建立了RhAG的同源欧洲亚硝化单胞菌Rh 50蛋白，并表明，这些突变可能会导致孔的开放。虽然RhAG的功能仍然存在争议，但功能性RhAG突变的首次报告支持RhAG作为阳离子孔的作用。（血。2009; 113：1350-1357）
Overhydrated hereditary stomatocytosis (OHSt) is a rare dominantly inherited hemolytic anemia characterized by a profuse membrane leak to monovalent cations. Here, we show that OHSt red cell membranes contain slightly reduced amounts of Rh-associated glycoprotein (RhAG), a putative gas channel protein. DNA analysis revealed that the OHSt patients have 1 of 2 heterozygous mutations (t182g, t194c) in RHAG that lead to substitutions of 2 highly conserved amino acids (Ile61Arg, Phe65Ser). Unexpectedly, expression of wild-type RhAG in Xenopus laevis oocytes induced a monovalent cation leak; expression of the mutant RhAG proteins induced a leak about 6 times greater than that in wild type. RhAG belongs to the ammonium transporter family of proteins that form pore-like structures. We have modeled RhAG on the homologous Nitrosomonas europaea Rh50 protein and shown that these mutations are likely to lead to an opening of the pore. Although the function of RhAG remains controversial, this first report of functional RhAG mutations supports a role for RhAG as a cation pore. (Blood. 2009; 113: 1350-1357)