Fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva
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DOI：
10.1016/j.berh.2007.11.007
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发表时间：
2008-03-01
影响因子：
5.2
通讯作者：
Groppe, Jay
中科院分区：
文献类型：
--
作者：
Kaplan, Frederick S.;Le Merrer, Martine;Groppe, Jay
进行性骨化性纤维发育不良（Fibrodysplasia ossificans progressiva，FOP）是一种罕见的先天性骨骼畸形和进行性异位骨化（progressive heterotopic ossification，HO）的遗传性疾病，是人类最严重的HO疾病。软组织损伤会促使疾病发作，并且不动是累积的。最近，激活素受体1A/激活素样激酶2（ACVR 1/ALK 2），一种骨形态发生蛋白（BMP）I型受体的复发性突变在所有散发性和家族性经典FOP病例中均有报道，使其成为人类基因组中最具特异性的致病突变之一。FOP基因的发现建立了理解FOP的关键里程碑，揭示了转化生长因子（TGF）-β/BMP信号通路中药物开发的高度保守靶点，并推动了ACVR 1/ALK 2小分子信号转导抑制剂的开发治疗方法。目前的治疗包括早期诊断，努力避免医源性损害，以及疼痛发作的症状改善。FOP的有效治疗，以及可能用于HO的其他常见疾病，可能基于阻断ACVR 1/ALK 2信号传导的未来干预。
Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition of congenital skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic disorder of HO in humans. Episodic disease flare-ups are precipitated by soft tissue injury, and immobility is cumulative. Recently, a recurrent mutation in activin receptor 1A/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved target for drug development in the transforming growth factor (TGF)-beta/BMP signalling pathway, and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for ACVR1/ALK2. Present management involves early diagnosis, assiduous avoidance of iatrogenic harm, and symptomatic amelioration of painful flare-ups. Effective therapies for FOP, and possibly for other common conditions of HO, may potentially be based on future interventions that block ACVR1/ALK2 signalling.