Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan; Division of Orthodontics, Department of Human Development and Fostering, Meikai University School of Dentistry, Saitama, Japan.
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan; Project of Clinical and Basic Research for FOP, Saitama Medical University, Saitama, Japan.
Bone. 2018 Jun;111:101-108. doi: 10.1016/j.bone.2018.03.015. Epub 2018 Mar 15.
Various substitution mutations in ALK2, a transmembrane serine/threonine kinase receptor for bone morphogenetic proteins (BMPs), have been identified in patients with genetic disorders such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG) and heart defects. In this study, we characterized the ALK2 mutants R258G, G328V and F246Y, which were identified in patients with severe FOP, DIPG and unusual hereditary skeletal dysplasia, respectively. Both R258G and G328V were gain-of-function mutations, but F246Y was equivalent to wild-type ALK2. We also examined the effect of the suppressor FKBP12 on the signal transduction of a further 14 ALK2 mutations associated with FOP and/or DIPG. To varying extents FKBP12 over-expression suppressed the basal signaling induced by thirteen of the ALK2 mutants, whereas PF197-8L was uniquely resistant. In the PF197-8L mutant, the modelled ALK2 residue L197 induced a steric clash with the D36 residue in FKBP12 and dissociated their interaction. The co-expression of BMP type II receptors or stimulation with ligands relieved the suppression by FKBP12 by disrupting the interaction between mutant ALK2 and FKBP12. Taken together, FKBP12 binds to and suppresses mutant ALK2 proteins associated with FOP and DIPG, except for PF197-8L.
ALK2 是一种跨膜丝氨酸/苏氨酸激酶受体，可与骨形态发生蛋白（BMPs）结合。在纤维发育不良性骨化性纤维瘤（FOP）、弥漫性内在脑桥胶质瘤（DIPG）和心脏缺陷等遗传疾病患者中，已发现其存在各种替代突变。在这项研究中，我们对在严重 FOP、DIPG 和不寻常遗传性骨骼发育不良患者中鉴定出的 ALK2 突变体 R258G、G328V 和 F246Y 进行了特征描述。R258G 和 G328V 均为获得功能突变体，但 F246Y 与野生型 ALK2 等效。我们还研究了 FKBP12 抑制剂对与 FOP 和/或 DIPG 相关的另外 14 种 ALK2 突变体信号转导的影响。FKBP12 过表达在不同程度上抑制了 13 种 ALK2 突变体诱导的基础信号，而 PF197-8L 除外。在 PF197-8L 突变体中，建模的 ALK2 残基 L197 与 FKBP12 中的 D36 残基发生空间冲突，从而使其相互作用解离。共表达 BMP 型 II 受体或用配体刺激可通过破坏突变型 ALK2 与 FKBP12 之间的相互作用，从而减轻 FKBP12 的抑制作用。总之，FKBP12 结合并抑制与 FOP 和 DIPG 相关的突变型 ALK2 蛋白，PF197-8L 除外。
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