Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy.
UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.
Int J Mol Sci. 2018 Mar 26;19(4):989. doi: 10.3390/ijms19040989.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is , encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation.
进行性骨化性纤维发育不良（FOP）是一种罕见的遗传性疾病，其特征是进行性的骨骼外骨化，导致进行性累积和严重残疾。FOP 的病程极其多变且呈间歇性，可由创伤、感染、医源性损伤、免疫接种诱发，也可无明显诱因突发。致病基因为 ，编码骨形态发生蛋白（BMPs）的 Alk-2 型 I 受体。信号由 BMP 与由 I 型和 II 型分子组成的受体复合物结合起始，并可通过两条主要途径进入细胞，即经典的 SMAD 依赖性信号通路和 p38 介导的级联反应。大多数 FOP 患者携带受体甘氨酸-丝氨酸丰富（GS）结构域中反复出现的 R206H 取代，而其他一些突变则导致少数病例发生。突变导致下游 BMP 依赖性途径失调，使突变型 ACVR1 对非经典配体激活素 A 产生反应。目前尚无针对 FOP 的病因治疗方法。然而，目前正在进行许多努力，以寻找针对受体活性和下游异常途径的特定治疗方法，这些方法可在不同水平上靶向细胞成分和/或过程，从而改变导致新骨形成的局部环境。
