致病性突变图谱为pendrin（SLC26A4）跨膜结构域提出了一种创新的结构模型。

Mapping pathogenic mutations suggests an innovative structural model for the pendrin (SLC26A4) transmembrane domain.

作者信息

Bassot Claudio, Minervini Giovanni, Leonardi Emanuela, Tosatto Silvio C E

机构信息

Dept. of Biomedical Sciences, CRIBI Biotechnology Center, University of Padua, Italy.

Dept. of Woman and Child Health, University of Padua, Italy.

出版信息

Biochimie. 2017 Jan;132:109-120. doi: 10.1016/j.biochi.2016.10.002. Epub 2016 Oct 19.

DOI:10.1016/j.biochi.2016.10.002

PMID:27771369

Abstract

Human pendrin (SLC26A4) is an anion transporter mostly expressed in the inner ear, thyroid and kidney. SLC26A4 gene mutations are associated with a broad phenotypic spectrum, including Pendred Syndrome and non-syndromic hearing loss with enlarged vestibular aqueduct (ns-EVA). No experimental structure of pendrin is currently available, making phenotype-genotype correlations difficult as predictions of transmembrane (TM) segments vary in number. Here, we propose a novel three-dimensional (3D) pendrin transmembrane domain model based on the SLC26Dg transporter. The resulting 14 TM topology was found to include two non-canonical transmembrane segments crucial for pendrin activity. Mutation mapping of 147 clinically validated pathological mutations shows that most affect two previously undescribed TM regions.

摘要

人耳内肽转运体（SLC26A4）是一种阴离子转运蛋白，主要在内耳、甲状腺和肾脏中表达。SLC26A4基因突变与广泛的表型谱相关，包括彭德莱德综合征和伴有前庭导水管扩大的非综合征性听力损失（ns-EVA）。目前尚无耳内肽的实验结构，由于跨膜（TM）片段数量的预测各不相同，使得表型-基因型相关性分析变得困难。在此，我们基于SLC26Dg转运体提出了一种新型的耳内肽跨膜结构域三维（3D）模型。结果发现，由此产生的14个TM拓扑结构包括两个对耳内肽活性至关重要的非典型跨膜片段。对147个经临床验证的病理性突变进行的突变图谱分析表明，大多数突变影响两个以前未描述的TM区域。