Nephrogenic diabetes insipidus: Functional analysis of new AVPR2 mutations identified in Italian families
Nephrogenic diabetes insipidus: Functional analysis of new AVPR2 mutations identified in Italian families
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DOI：
10.1681/asn.v1161033
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发表时间：
2000-06-01
影响因子：
13.6
通讯作者：
Chini, B
中科院分区：
文献类型：
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作者：
Albertazzi, E;Zanchetta, D;Chini, B
本研究的目的是确定受 X 连锁肾性尿崩症 (NDI) 影响的意大利患者 V2 加压素受体基因 (AVPR2) 的功能丧失突变。在所研究的 18 个不相关家族中，有 15 个发现了突变：其中 9 个突变以前是未知的，包括位于已知对确定受体药理学特性很重要的区域的两个影响残基，因此对这些突变进行了功能研究。第一个 (A84D) 涉及位于天冬氨酸 (D85) 附近的残基，该残基在所有 G 蛋白偶联受体中高度保守，并且被认为在其异构化为功能活性和非活性状态的过程中发挥作用。目前的研究表明，这种突变不仅影响受体折叠，导致其保留在细胞内区室中，而且正如预期的那样，还对其结合和偶联特性产生深远的影响。第二个是位于第一个细胞外环（W99R）起始处的色氨酸突变，该突变极大地损害了受体的结合特性，并且对其细胞内路径影响较小。对带有该突变的第一个细胞外环的分子分析表明，该残基在稳定肽/受体相互作用方面发挥着重要作用，而肽/受体相互作用负责激动剂与 V2 受体的高亲和力结合。
The aim of this study was to identify loss-of-function mutations of the V2 vasopressin receptor gene (AVPR2) in Italian patients affected by X-linked nephrogenic diabetes insipidus (NDI). Mutations were found in 15 of the 18 unrelated families investigated: nine of these mutations were previously unknown, including two affecting residues located in regions known to be important for determining the pharmacologic properties of the receptor, which were therefore functionally investigated. The first (A84D) involves a residue located near an aspartic acid (D85) that is highly conserved in all G protein-coupled receptors and that is believed to play a role in the process of their isomerization into functionally active and inactive states. The present study indicates that this mutation not only affects receptor folding in such a way as to lead to its retention inside the intracellular compartments but, as expected, also has profound effects on its binding and coupling properties. The second was a mutation of a tryptophan located at the beginning of the first extracellular loop (W99R) that greatly impaired the binding properties of the receptor and had a minor effect on its intracellular routing. Molecular analysis of the first extracellular loop bearing this mutation suggests that this residue plays a fundamental role in stabilizing the peptide/ receptor interactions responsible for the high-affinity binding of agonists to the V2 receptor.