Yoon J S, Park H-J, Yoo S-Y, Namkung W, Jo M J, Koo S K, Park H-Y, Lee W-S, Kim K H, Lee M G
Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
J Med Genet. 2008 Jul;45(7):411-9. doi: 10.1136/jmg.2007.054635. Epub 2008 Feb 29.
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.
A total of 11 non-synonymous disease associated mutations were generated and their effects on protein processing and on ion transporting activities were examined.
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.
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.
SLC26A4基因突变可导致 Pendred 综合征和非综合征性听力损失（DFNB4）。本研究分析了东亚人群中新发现的非同义SLC26A4突变以及高加索人群中的三种常见突变，以表征其分子致病机制并探索挽救其加工缺陷的可能性。
共产生了11种与疾病相关的非同义突变，并检测了它们对蛋白质加工和离子转运活性的影响。
大多数突变导致SLC26A4基因产物（pendrin）滞留在内质网区域，而野生型pendrin可到达质膜。因此，这些突变消除了pendrin的复合糖基化和Cl(-)/HCO(3)(-)交换活性。然而，观察到突变pendrin分子在加工过程中存在显著异质性。每种突变蛋白表现出不同的细胞定位、不同程度的N-糖基化以及对挽救加工缺陷的处理的不同程度的敏感性。例如，东亚人群中最常见的突变H723R-pendrin主要在内质网中表达，通过低温孵育可显著恢复其蛋白质加工和离子转运活性的缺陷。另一方面，高加索人群中最常见的突变L236P-pendrin主要位于中心体区域，且对温度不敏感。
这些结果表明，pendrin突变蛋白的加工由突变特异性机制决定，并且需要一种突变特异性方法来挽救每个折叠突变体的构象缺陷。
