A novel mutant Na+/HCO3- cotransporter NBCe1 in a case of compound-heterozygous inheritance of proximal renal tubular acidosis
A novel mutant Na+/HCO3- cotransporter NBCe1 in a case of compound-heterozygous inheritance of proximal renal tubular acidosis
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DOI：
10.1113/jp272252
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发表时间：
2016-11-01
影响因子：
5.5
通讯作者：
Parker, Mark D.
中科院分区：
文献类型：
--
作者：
Myers, Evan J.;Yuan, Lu;Parker, Mark D.
近端肾小管性酸中毒(PRTA)是一种罕见的隐性遗传性疾病，以异常酸性血液、失明以及低于平均身高和体重为特征。PRTA通常与溶质携带者4家族基因SLC4A4的纯合突变有关。SLC4A4编码碳酸氢钠共转运蛋白NBCe1，这是一种维持细胞内和血浆pH的膜蛋白。我们提出的第一个描述的情况下，复合杂合遗传的PRTA。该个体在NBCe1中遗传了两个突变：p.Arg510His(R510H)和p.Gln913Arg(Q913R)，父母各一个。除了PRTA的常见特征外，患者还表现出不寻常的体征，如肌肉痉挛和发烧。我们已经重建了这些突变的转运蛋白，以便在模型系统中表达。我们发现，这两种突变蛋白在哺乳动物肾细胞系中表达时都表现出显著的细胞内滞留。当在非洲爪哇卵母细胞中表达时，我们发现R510H和Q913R突变的NBCe1分子表现出明显的正常的Na+/HCO3共转运活性，但Q913R与不依赖HCO3的异常阴离子泄漏有关。我们得出结论，NBCe1蛋白在近端小管上皮细胞基侧膜上积聚的减少是该病例中PRTA的最可能原因。我们进一步注意到，如果在哺乳动物细胞的质膜上表达，与Q913R相关的阴离子泄漏本身可能是致病的，这损害了旨在增加突变的NBCe1在质膜中积累的策略的好处。
Proximal renal tubular acidosis (pRTA) is a rare, recessively-inherited disease characterized by abnormally acidic blood, blindness, as well as below average height and weight. pRTA is typically associated with homozygous mutation of the solute carrier 4 family gene SLC4A4. SLC4A4 encodes the electrogenic sodium bicarbonate cotransporter NBCe1, a membrane protein that acts to maintain intracellular and plasma pH. We present the first description of a case of compound-heterozygous inheritance of pRTA. The individual has inherited two mutations in NBCe1: p.Arg510His (R510H) and p.Gln913Arg (Q913R), one from each parent. In addition to the usual features of pRTA, the patient exhibits unusual signs, such as muscle spasms and fever. We have recreated these mutant transporters for expression in model systems. We find that both of the mutant proteins exhibit substantial intracellular retention when expressed in mammalian renal cell lines. When expressed in Xenopus oocytes, we find that the R510H and Q913R-mutant NBCe1 molecules exhibit apparently normal Na+/HCO3- cotransport activity but that Q913R is associated with an unusual HCO3- independent anion-leak. We conclude that a reduced accumulation of NBCe1 protein in the basolateral membrane of proximal-tubule epithelia is the most probable cause of pRTA in this case. We further note that the Q913R-associated anion-leak could itself be pathogenic if expressed in the plasma membrane of mammalian cells, compromising the benefit of strategies aiming to enhance mutant NBCe1 accumulation in the plasma membrane.