Heterogeneity in the processing defect of SLC26A4 mutants
Heterogeneity in the processing defect of SLC26A4 mutants
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DOI：
10.1136/jmg.2007.054635
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发表时间：
2008-07-01
影响因子：
4
通讯作者：
Lee, M. G.
中科院分区：
文献类型：
--
作者：
Yoon, J. S.;Park, H-J;Lee, M. G.
背景：SLC26A4基因突变与Pendred综合征和非综合征性耳聋(DFNB4)有关。本研究分析了在东亚人群中新发现的SLC26A4非同义突变，以及在高加索人群中发现的三个常见突变，以表征其分子致病机制，并探索挽救其加工缺陷的可能性。方法：共产生11个非同义疾病相关突变，并检测其对蛋白质加工和离子转运活性的影响。结果：大多数突变导致SLC26A4基因产物(垂蛋白)滞留在细胞内，而野生型垂蛋白则到达质膜。相应地，这些突变取消了侧翼蛋白的复杂糖基化和Cl(-)/HCO(3)(-)交换活性。然而，在突变型侧链蛋白分子的加工过程中观察到了显著的异质性。每个突变蛋白都表现出不同的细胞定位，不同程度的N-糖基化，以及对修复加工缺陷的治疗的不同程度的敏感性。例如，东亚人最常见的突变H723R-Pendrin主要表达在内质网(ER)，其在蛋白质加工和离子转运活性方面的缺陷通过低温孵育得到了相当大的恢复。另一方面，L236P-Pendrin是高加索人中最常见的突变，主要位于中心体区域，对温度不敏感。结论：Pendrin突变体蛋白的加工是由突变体特有的机制决定的，需要突变特异性的方法来挽救每个折叠突变体的构象缺陷。
Background: Mutations in the SLC26A4 gene are responsible for Pendred syndrome and non-syndromic hearing loss (DFNB4). This study analysed non-synonymous SLC26A4 mutations newly identified in East Asians, as well as three common mutations in Caucasians, to characterise their molecular pathogenic mechanisms and to explore the possibility of rescuing their processing defects.Methods: A total of 11 non-synonymous disease associated mutations were generated and their effects on protein processing and on ion transporting activities were examined.Results: Most of the mutations caused retention of the SLC26A4 gene product ( pendrin) in the intracellular region, while wild-type pendrin reached the plasma membrane. Accordingly, these mutations abolished complex glycosylation and Cl(-)/HCO(3)(-) exchange activities of pendrin. However, significant heterogeneity in the processing of mutant pendrin molecules was observed. Each mutant protein exhibited a different cellular localisation, a different degree of N-glycosylation, and a different degree of sensitivity to the treatments that rescue processing defects. For example, H723R-pendrin, the most common mutation in East Asians, was mostly expressed in endoplasmic reticulum ( ER), and its defects in protein processing and ion transporting activities were restored considerably by low temperature incubation. On the other hand, L236P-pendrin, the most common mutation in Caucasians, was mainly in the centrosomal region and was temperature insensitive.Conclusion: These results indicate that the processing of pendrin mutant protein is determined by mutant specific mechanisms, and that a mutant specific method would be required to rescue the conformational defects of each folding mutant.