Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China.
JCI Insight. 2017 Feb 9;2(3):e91079. doi: 10.1172/jci.insight.91079.
Heterotrimeric G proteins play critical roles in transducing extracellular signals generated by 7-transmembrane domain receptors. Somatic gain-of-function mutations in G protein α subunits are associated with a variety of diseases. Recently, we identified gain-of-function mutations in Gα in patients with autosomal-dominant hypocalcemia type 2 (ADH2), an inherited disorder of hypocalcemia, low parathyroid hormone (PTH), and hyperphosphatemia. We have generated knockin mice harboring the point mutation c.C178T (p.Arg60Cys) identified in ADH2 patients. The mutant mice faithfully replicated human ADH2. They also exhibited low bone mineral density and increased skin pigmentation. Treatment with NPS 2143, a negative allosteric modulator of the calcium-sensing receptor (CASR), increased PTH and calcium concentrations in WT and mutant mice, suggesting that the gain-of-function effect of GNA11 is partly dependent on coupling to the CASR. Treatment with the Gα-specific inhibitor YM-254890 increased blood calcium in heterozygous but not in homozygous mice, consistent with published crystal structure data showing that Arg60 forms a critical contact with YM-254890. This animal model of ADH2 provides insights into molecular mechanism of this G protein-related disease and potential paths toward new lines of therapy.
异三聚体 G 蛋白在转导由 7 次跨膜受体产生的细胞外信号中发挥关键作用。G 蛋白 α 亚基的体细胞获得性功能突变与多种疾病有关。最近，我们在常染色体显性低钙血症 2 型（ADH2）患者中发现了 Gα的获得性功能突变，ADH2 是一种低钙、低甲状旁腺激素（PTH）和高磷血症的遗传性疾病。我们已经生成了携带在 ADH2 患者中发现的点突变 c.C178T（p.Arg60Cys）的基因敲入小鼠。突变小鼠忠实地复制了人类 ADH2。它们还表现出低骨密度和增加的皮肤色素沉着。用 NPS 2143（钙敏感受体（CASR）的负变构调节剂）治疗 WT 和突变小鼠，增加了 PTH 和钙浓度，表明 GNA11 的获得性功能效应部分依赖于与 CASR 的偶联。用 Gα 特异性抑制剂 YM-254890 治疗杂合子但不治疗纯合子 小鼠增加了血钙，这与已发表的晶体结构数据一致，表明 Arg60 与 YM-254890 形成了一个关键接触。ADH2 的这种动物模型为这种与 G 蛋白相关的疾病的分子机制提供了深入了解，并为新的治疗方法提供了潜在途径。
