ACVR1 p.Q207E causes classic fibrodysplasia ossificans progressiva and is functionally distinct from the engineered constitutively active ACVR1 p.Q207D variant
ACVR1 p.Q207E causes classic fibrodysplasia ossificans progressiva and is functionally distinct from the engineered constitutively active ACVR1 p.Q207D variant
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DOI：
10.1093/hmg/ddu255
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发表时间：
2014-10-15
影响因子：
3.5
通讯作者：
Seemann, Petra
中科院分区：
文献类型：
--
作者：
Haupt, Julia;Deichsel, Alexandra;Seemann, Petra
进行性骨化性纤维发育不良（FOP）是一种进行性异位骨化（HO）的致残性遗传性疾病。在此，我们报道了一名患者，其具有一种极其罕见的点突变[c.619C>G，p.Q207E]，该突变位于与激活素A受体1型（ACVR1）最常见的FOP突变[c.617G>A，p.R206H]相邻的一个密码子上，并且在GS激活域中影响与工程化组成型激活（c.a.）变体p.Q207D相同的细胞内氨基酸位置。据预测，残基207处的两种突变通过引入负电荷具有相似的功能效应。转基因p.Q207D - c.a.小鼠在多项体内研究中已作为FOP HO的模型。然而，我们发现当在鸡肢体中过表达以及在软骨形成、骨形成和肌形成的分化测定中，工程化的ACVR1(Q207D - c.a.)比经典的FOP突变ACVR1(R206H)具有显著更高的活性。重要的是，我们的研究表明，在这些测定中ACVR1(Q207E)类似于经典的FOP受体，而不是工程化的ACVR1(Q207D - c.a.)。值得注意的是，报告基因测定显示，两种天然存在的FOP受体（ACVR1(R206H)和ACVR1(Q207E)）均被BMP7激活，并且对配体结合域的缺失敏感，而工程化的ACVR1(Q207D - c.a.)则表现出配体非依赖活性。我们进行了计算机模拟分析，并提出了p.Q207D - c.a.的结构模型，该模型将GS域不可逆地重新定位到激活位置，使其变得不依赖配体。我们得出结论，工程化的p.Q207D - c.a.突变作为FOP的模型存在严重局限性，而天然存在的突变p.R206H和p.Q207E促进受体激活，尽管是以可逆的方式。
Fibrodysplasia ossificans progressiva (FOP) is a disabling genetic disorder of progressive heterotopic ossification (HO). Here, we report a patient with an ultra-rare point mutation [c.619C>G, p.Q207E] located in a codon adjacent to the most common FOP mutation [c.617G>A, p.R206H] of Activin A Receptor, type 1 (ACVR1) and that affects the same intracellular amino acid position in the GS activation domain as the engineered constitutively active (c.a.) variant p.Q207D. It was predicted that both mutations at residue 207 have similar functional effects by introducing a negative charge. Transgenic p.Q207D-c.a. mice have served as a model for FOP HO in several in vivostudies. However, we found that the engineered ACVR1(Q207D-c.a.) is significantly more active than the classic FOP mutation ACVR1(R206H) when overexpressed in chicken limbs and in differentiation assays of chondrogenesis, osteogenesis and myogenesis. Importantly, our studies reveal that the ACVR1(Q207E) resembles the classic FOP receptor in these assays, not the engineered ACVR1(Q207D-c.a). Notably, reporter gene assays revealed that both naturally occurring FOP receptors (ACVR1(R206H) and ACVR1(Q207E)) were activated by BMP7 and were sensitive to deletion of the ligand binding domain, whereas the engineered ACVR1(Q207D-c.a). exhibited ligand independent activity. We performed an in silico analysis and propose a structural model for p.Q207D-c.a. that irreversibly relocates the GS domain into an activating position, where it becomes ligand independent. We conclude that the engineered p.Q207D-c.a. mutation has severe limitations as a model for FOP, whereas the naturally occurring mutations p.R206H and p.Q207E facilitate receptor activation, albeit in a reversible manner.