Institute for Research in Immunology and Cancer, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal, Québec, Canada.
J Am Soc Nephrol. 2012 Oct;23(10):1635-40. doi: 10.1681/ASN.2012010077. Epub 2012 Sep 6.
Gain-of-function mutations in the gene encoding the V2 vasopressin receptor (V2R) cause nephrogenic syndrome of inappropriate antidiuresis. To date, reported mutations lead to the substitution of arginine 137 by either a cysteine or leucine (R137C/L). Here, we describe a 3-month-old hyponatremic infant found to have a phenylalanine 229 to valine (F229V) substitution in V2R. Characterization of this substitution in vitro revealed that it leads to high constitutive activity of the receptor, compatible with spontaneous antidiuresis. In contrast to R137C/L mutant receptors, F229V receptors do not undergo spontaneous desensitization, which results in sustained, high basal activity. Notably, the V2R-selective inverse agonists tolvaptan and satavaptan completely silenced the constitutive signaling activity of the F229V mutant receptor, indicating that this substitution does not lock the receptor in an irreversible active state. Thus, inverse agonists might prove to be effective therapies for treating patients with this or other spontaneously activating mutations that do not lock the V2R in its active state. These results emphasize the importance of genetic testing and the functional characterization of mutant receptors for patients with nephrogenic syndrome of inappropriate antidiuresis because the results might inform treatment decisions.
编码血管加压素受体 2（V2R）的基因中的功能获得性突变可导致抗利尿激素分泌不当的肾源性尿崩症。迄今为止，报道的突变导致精氨酸 137 被半胱氨酸或亮氨酸取代（R137C/L）。在这里，我们描述了一名 3 个月大的低钠血症婴儿，其 V2R 中的苯丙氨酸 229 被缬氨酸取代（F229V）。该突变的体外特性表明，它导致受体的高组成型活性，与自发性抗利尿作用一致。与 R137C/L 突变受体不同，F229V 受体不会自发脱敏，从而导致持续的高基础活性。值得注意的是，V2R 选择性反向激动剂托伐普坦和沙他伐坦完全沉默了 F229V 突变受体的组成型信号转导活性，表明该取代不会使受体锁定在不可逆的活性状态。因此，反向激动剂可能被证明是治疗患有这种或其他不锁定 V2R 处于活性状态的自发性激活突变的患者的有效疗法。这些结果强调了对患有抗利尿激素分泌不当的肾源性尿崩症的患者进行基因测试和突变受体功能特征分析的重要性，因为结果可能会影响治疗决策。
