Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy.
Department of Genetics and Molecular Medicine, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Mol Genet Genomic Med. 2021 Oct;9(10):e1774. doi: 10.1002/mgg3.1774. Epub 2021 Aug 4.
Fibrodysplasia Ossificans Progressiva (FOP) is a rare autosomal dominant disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues leading to cumulative disability. The genetic cause of FOP are mutations in the ACVR1 gene that encodes a type I receptor of Bone Morphogenetic Proteins. The most recurrent mutation in FOP patients is R206H affecting the Glycine-Serine rich domain and causing the hyper-activation of the receptor and the responsivity to the non-canonical ligand, Activin A. In the present study, we described a 3-years old child with early and highly suggestive clinical features of FOP who was found negative for the recurrent p.R206H substitution.
Molecular screening of the whole ACVR1 coding sequence and functional characterization in transfection-based assays.
We identified a novel, de novo variant in the fifth ACVR1 coding exon (NM_001111067.4:c.772A>T; NP_001104537.1:p.(R258W)). This substitution, never reported in association with FOP, affects a conserved arginine residue in the kinase domain of the protein. In silico analysis predicted the pathogenicity of this substitution, demonstrated by in vitro assays showing that the p.R258W ACVR1 mutated receptor acquires the ability to transduce the aberrant Activin A-mediated signaling, as observed for the gene variants associated with FOP.
纤维性骨发育不良（FOP）是一种罕见的常染色体显性遗传病，其特征为大脚趾先天性畸形和软组织进行性异位骨化，导致逐渐丧失能力。FOP 的遗传原因是 ACVR1 基因的突变，该基因编码骨形态发生蛋白的 I 型受体。FOP 患者中最常见的突变是 R206H，影响甘氨酸-丝氨酸丰富结构域，导致受体过度激活，并对非典型配体激活素 A 产生反应。在本研究中，我们描述了一名 3 岁儿童，其临床表现高度提示 FOP，但其 ACVR1 基因 p.R206H 替代的反复出现为阴性。
对整个 ACVR1 编码序列进行分子筛选，并在基于转染的测定中进行功能表征。
我们在第五个 ACVR1 编码外显子中发现了一个新的、从头发生的变异（NM_001111067.4:c.772A>T；NP_001104537.1:p.(R258W)）。该替代从未与 FOP 相关报道，影响蛋白激酶结构域中的保守精氨酸残基。计算机分析预测了该替代的致病性，通过体外实验证明了 p.R258W ACVR1 突变受体获得了传递异常激活素 A 介导的信号的能力，正如与 FOP 相关的基因变异所观察到的那样。
