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, Köster Bernhard, Pauli Richard M, Reardon William, Zaidi Syed-Adeel, Zasloff Michael, Morhart Rolf, Mundlos Stefan, Groppe Jay, Shore Eileen M
Department of Orthopaedic Surgery, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6081, USA.
Hum Mutat. 2009 Mar;30(3):379-90. doi: 10.1002/humu.20868.
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 glycine and serine residue (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.
进行性骨化性纤维发育不良（FOP）是一种常染色体显性遗传的人类骨形成障碍疾病，可导致发育性骨骼缺陷，并在儿童期引发软结缔组织内广泛的致残性骨形成（异位骨化）。此前发现，所有具有FOP典型临床特征（大脚趾畸形和进行性异位骨化）的患者在激活素A I型受体/激活素样激酶2（ACVR1/ALK2，一种骨形态发生蛋白（BMP）I型受体）的甘氨酸和丝氨酸残基（GS）激活域中携带相同的杂合突变（c.617G>A；p.R206H）。在具有FOP样异位骨化和/或脚趾畸形的患者中，我们识别出了临床特征不符合FOP的患者。这些非典型FOP患者分为两类：FOP加型（FOP的典型定义特征加上一个或多个非典型特征）和FOP变异型（FOP的两个典型定义特征中的一个或两个出现重大变异）。所有接受检查的患者在保守氨基酸中都有杂合ACVR1错义突变。虽然在所有经典FOP病例和大多数FOP加型病例中都发现了复发性c.617G>A；p.R206H突变，但新型ACVR1突变出现在FOP变异型和两例FOP加型病例中。蛋白质结构同源性建模预测，每个氨基酸替换都会激活ACVR1蛋白以增强受体信号传导。我们观察到一些ACVR1突变与异位骨化发病年龄或胚胎骨骼发育之间存在基因型-表型相关性。
