Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis
Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis
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DOI：
10.1038/ki.2015.181
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发表时间：
2015-11-01
影响因子：
19.6
通讯作者：
Hunyady, Laszlo
中科院分区：
文献类型：
--
作者：
Erdelyi, Laszlo S.;Mann, W. Alexander;Hunyady, Laszlo
不适当抗利尿肾源性综合征 (NSIAD) 是一种最近发现的罕见疾病，由 V2 加压素受体基因 AVPR2 的功能获得性突变引起。迄今为止，Phe229 和 Arg137 的突变已被确定为 V2 加压素受体 (V2R) 的功能获得性。这些受体突变会导致低钠血症，从而可能导致婴儿出现临床症状。在这里，我们提出了一个家族中 V2R 基因外显子 2 中新发现的 I130N 取代，该取代导致 NSIAD。该 I130N 突变导致 HEK293 细胞中 V2R 具有组成型活性，并产生组成型环磷酸腺苷 (cAMP)。这种基础活性可以被反向激动剂托伐普坦阻断，并且精氨酸-加压素刺激增强了 I130N-V2R 的 cAMP 产生。该突变会导致受体构象出现偏差，因为 I130N 的基础 cAMP 生成活性不会导致与 β-arrestin 相互作用。突变受体的组成型活性引起组成型动力依赖型和β-抑制蛋白独立型内化。使用显性失活动力抑制基础内化导致细胞表面表达增加。与组成型内化相反，激动剂诱导的内吞作用是β-抑制蛋白依赖性的。因此，托伐普坦可用于治疗携带 I130N-V2R 突变的 NSIAD 患者的低钠血症。
Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently discovered rare disease caused by gain-of-function mutations of the V2 vasopressin receptor gene, AVPR2. To date, mutations of Phe229 and Arg137 have been identified as gain-of-function in the V2 vasopressin receptor (V2R). These receptor mutations lead to hyponatremia, which may lead to clinical symptoms in infants. Here we present a newly identified I130N substitution in exon 2 of the V2R gene in a family, causing NSIAD. This I130N mutation resulted in constitutive activity of the V2R with constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells. This basal activity could be blocked by the inverse agonist tolvaptan and arginine-vasopressin stimulation enhanced the cAMP production of I130N-V2R. The mutation causes a biased receptor conformation as the basal cAMP generation activity of I130N does not lead to interaction with beta-arrestin. The constitutive activity of the mutant receptor caused constitutive dynamin-dependent and beta-arrestin-independent internalization. The inhibition of basal internalization using dominant-negative dynamin resulted in an increased cell surface expression. In contrast to the constitutive internalization, agonist-induced endocytosis was beta-arrestin dependent. Thus, tolvaptan could be used for treatment of hyponatremia in patients with NSIAD who carry the I130N-V2R mutation.