Molecular mechanisms of autosomal dominant and recessive distal renal tubular acidosis caused by SLC4A1 (AE1) mutations.
Molecular mechanisms of autosomal dominant and recessive distal renal tubular acidosis caused by SLC4A1 (AE1) mutations.
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DOI：
10.4172/1747-0862.1000013
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发表时间：
2005-11-16
期刊：
影响因子：
--
通讯作者：
Reithmeier RA
中科院分区：
文献类型：
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作者：
Yenchitsomanus PT;Kittanakom S;Rungroj N;Cordat E;Reithmeier RA
编码肾阴离子（Cl−/HCO 3 −）交换器1（kAE 1或带3）的SLC 4A 1（AE 1）突变可导致常染色体显性（AD）或常染色体隐性（AR）远端肾小管酸中毒（dRTA）。与SLC 4A 1突变相关的分子机制导致了这些不同的遗传模式，现在正在使用转染细胞系统揭示。显性突变体kAE 1 R589 H、R901 X和S613 F在培养的非极化和极化细胞中具有正常或不显著的阴离子转运功能变化，表现出内质网（ER）定位的细胞内滞留，而显性突变体kAE 1 R901 X和G609 R在培养的极化细胞中除了基底侧膜之外还错误地靶向顶膜。显性负效应可能是显性疾病的原因，因为kAE 1突变体和野生型蛋白质的异二聚体在细胞内保留。然而，隐性突变体kAE 1 G701 D和S773 P表现出明显的运输缺陷。kAE 1 G701 D突变体保留在高尔基体中，而错误折叠的kAE 1 S773 P，这是在ER出口受损，并被蛋白体降解，只能部分地传递到极化细胞的基底外侧膜。与显性突变体kAE 1相反，隐性突变体kAE 1和野生型kAE 1的异二聚体能够运输到质膜。因此，野生型kAE 1相对于隐性突变体kAE 1表现出“显性正效应”，因为它可以将突变蛋白从细胞内滞留中拯救出来，以在细胞表面表达。因此，需要纯合或复合杂合隐性突变来呈现疾病表型。使用dRTA动物模型的未来工作将提供对这种疾病的病理生理学的额外见解。
Mutations of SLC4A1 (AE1) encoding the kidney anion (Cl−/HCO3−) exchanger 1 (kAE1 or band 3) can result in either autosomal dominant (AD) or autosomal recessive (AR) distal renal tubular acidosis (dRTA). The molecular mechanisms associated with SLC4A1 mutations resulting in these different modes of inheritance are now being unveiled using transfected cell systems. The dominant mutants kAE1 R589H, R901X and S613F, which have normal or insignificant changes in anion transport function, exhibit intracellular retention with endoplasmic reticulum (ER) localization in cultured non-polarized and polarized cells, while the dominant mutants kAE1 R901X and G609R are mis-targeted to apical membrane in addition to the basolateral membrane in cultured polarized cells. A dominant-negative effect is likely responsible for the dominant disease because heterodimers of kAE1 mutants and the wild-type protein are intracellularly retained. The recessive mutants kAE1 G701D and S773P however exhibit distinct trafficking defects. The kAE1 G701D mutant is retained in the Golgi apparatus, while the misfolded kAE1 S773P, which is impaired in ER exit and is degraded by proteosome, can only partially be delivered to the basolateral membrane of the polarized cells. In contrast to the dominant mutant kAE1, heterodimers of the recessive mutant kAE1 and wild-type kAE1 are able to traffic to the plasma membrane. The wild-type kAE1 thus exhibits a ‘dominant-positive effect’ relative to the recessive mutant kAE1 because it can rescue the mutant proteins from intracellular retention to be expressed at the cell surface. Consequently, homozygous or compound heterozygous recessive mutations are required for presentation of the disease phenotype. Future work using animal models of dRTA will provide additional insight into the pathophysiology of this disease.