Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1.
Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1.
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DOI：
10.1002/humu.20868
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发表时间：
2009-03
期刊：
影响因子：
3.9
通讯作者：
Shore, Eileen M
中科院分区：
文献类型：
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作者：
Kaplan, Frederick S;Xu, Meiqi;Seemann, Petra;Connor, J Michael;Glaser, David L;Carroll, Liam;Delai, Patricia;Fastnacht-Urban, Elisabeth;Forman, Stephen J;Gillessen-Kaesbach, Gabriele;Hoover-Fong, Julie;Koster, Bernhard;Pauli, Richard M;Reardon, William;Zaidi, Syed-Adeel;Zasloff, Michael;Morhart, Rolf;Mundlos, Stefan;Groppe, Jay;Shore, Eileen M
进行性骨化性纤维发育不良（FOP）是一种常染色体显性人类骨形成疾病，可导致儿童期发育性骨骼缺陷和软结缔组织内广泛的衰弱性骨形成（异位骨化）。所有具有FOP典型临床特征（拇趾畸形和进行性异位骨化）的患者先前已发现在激活素A I型受体/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GS激活结构域中携带相同的杂合突变（c.617G>A; p.R206H）。在FOP样异位骨化和/或脚趾畸形患者中，我们发现了FOP不常见的临床特征。这些非典型FOP患者形成两类：FOP+（FOP的经典定义特征加上一个或多个非典型特征）和FOP变体（FOP的两个经典定义特征中的一个或两个的主要变化）。所有检查的患者在保守氨基酸中均存在杂合ACVR 1错义突变。虽然在所有经典FOP病例和大多数FOP-plus病例中发现了复发性c.617G>A; p.R206H突变，但在FOP变体和两例FOP-plus病例中出现了新的ACVR 1突变。蛋白质结构同源性建模预测，每个氨基酸取代激活ACVR 1蛋白，以增强受体信号传导。我们观察到一些ACVR 1突变与异位骨化或胚胎骨骼发育的发病年龄之间的基因型-表型相关性。
Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant human disorder of bone formation that causes developmental skeletal defects and extensive debilitating bone formation within soft connective tissues (heterotopic ossification) during childhood. All patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G>A; p.R206H) in the GS activation domain of activin A type I receptor/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. Among patients with FOP-like heterotopic ossification and/or toe malformations, we identified patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP-plus (classic defining features of FOP plus one or more atypical features) and FOP variants (major variations in one or both of the two classic defining features of FOP). All patients examined have heterozygous ACVR1 missense mutations in conserved amino acids. While the recurrent c.617G>A; p.R206H mutation was found in all cases of classic FOP and most cases of FOP-plus, novel ACVR1 mutations occur in the FOP variants and two cases of FOP-plus. Protein structure homology modeling predicts that each of the amino acid substitutions activates the ACVR1 protein to enhance receptor signaling. We observed genotype-phenotype correlation between some ACVR1 mutations and the age of onset of heterotopic ossification or on embryonic skeletal development.