Variable signaling activity by FOP ACVR1 mutations.
Variable signaling activity by FOP ACVR1 mutations.
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DOI：
10.1016/j.bone.2017.10.027
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发表时间：
2018-04
期刊：
影响因子：
4.1
通讯作者：
Shore EM
中科院分区：
文献类型：
--
作者：
Haupt J;Xu M;Shore EM
进行性骨化性纤维发育不良（FOP）是一种罕见的异位骨化遗传性疾病，大多数FOP患者在ACVR1基因上具有相同的致病突变，即R206H。然而，在少数FOP病例中还发现了ACVR1 BMP I型受体的其他突变，这些患者的病情往往比R206H突变患者更轻或更重。患者中已提出基因型 - 表型相关性，从而根据在不同受体结构域内的位置以及结构建模对FOP突变进行分类。然而，尽管每种突变都会通过BMP - pSmad1/5/8通路诱导信号增强，但这些FOP变异受体功能差异的分子机制仍未确定。我们现在证明，ACVR1受体激酶结构域内的FOP突变比ACVR1 GS结构域内的突变对低水平的BMP更敏感。我们的数据还证实了具有FOP ACVR1突变的细胞对BMP和激活素A配体都有反应。我们还确定，缺失配体结合结构域的具有FOP ACVR1突变的构建体相对于野生型ACVR1仍保留了增强的BMP - pSmad1/5/8通路激活，这支持突变受体可以通过不依赖配体的机制发挥作用，要么直接通过突变的ACVR1，要么通过间接机制。
Most patients with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of heterotopic ossification, have the same causative mutation in ACVR1, R206H. However, additional mutations within the ACVR1 BMP type I receptor have been identified in a small number of FOP cases, often in patients with disease of lesser or greater severity than occurs with R206H mutations. Genotype-phenotype correlations have been suggested in patients, resulting in classification of FOP mutations based on location within different receptor domains and structural modeling. However while each of the mutations induces increased signaling through the BMP-pSmad1/5/8 pathway, the molecular mechanisms underlying functional differences of these FOP variant receptors remained undetermined. We now demonstrate that FOP mutations within the ACVR1 receptor kinase domain are more sensitive to low levels of BMP than mutations in the ACVR1 GS domain. Our data additionally confirm responsiveness of cells with FOP ACVR1 mutations to both BMP and Activin A ligands. We also have determined that constructs with FOP ACVR1 mutations that are engineered without the ligand-binding domain retain increased BMP-pSmad1/5/8 pathway activation relative to wild-type ACVR1, supporting that the mutant receptors can function through ligand-independent mechanisms either directly through mutant ACVR1 or through indirect mechanisms.
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