ClinVar Genomic variation as it relates to human health

Flexion contracture (present) , Limitation of joint mobility (present) , Motor delay (present) , Hearing impairment (present) , Abnormal posturing (present) , Soft tissue swelling of interphalangeal joints (present) , Myositis disease (present) (less)

Fused cervical vertebrae (present) , Hallux valgus (present) , Hearing impairment (present) , Jaw swelling (present) , Mandibular pain (present) , Myositis disease (present) , Edema (present) (less)

Shore et al. (2006) identified heterozygosity for a 617G-A transition in the ACVR1 gene, resulting in an arg206-to-his (R206H) substitution. The mutation was found in all affected members of 7 families with fibrodysplasia ossificans progressiva (FOP; 135100) and in 32 of 32 de novo cases of FOP. Codon 206 is at the end of a highly conserved glycine-serine (GS) activation domain at the junction of the protein kinase domain. The GS domain is critical for binding and activation of SMAD signaling and is a binding site for FKBP12 (FKBP1A; 186945), an inhibitory protein that prevents leaky activation of the receptor in the absence of ligand. Protein homology modeling suggested that the R206H mutation may disrupt intramolecular interactions that stabilize ACVR1 and/or alter interactions between the GS domain and other signaling pathway molecules. Shore et al. (2006) noted that the R206H mutation may be one of the most specific codons in the human genome to be associated with a disease phenotype. In a 3-year-old Taiwanese girl with dysplasia of the first metatarsal bones and progressive heterotopic ossificans of the right thigh due to routine childhood immunizations and several inappropriate surgical interventions, Lin et al. (2006) identified a de novo R206H mutation in the ACVR1 gene. The mutation was not found in the unaffected parents and brother. Nakajima et al. (2007) identified the R206H mutation in 3 unrelated sporadic Japanese patients with FOP, indicating that this mutation is common and recurrent in the global population. The authors noted that mutation results from a CpG dinucleotide change. In 15 of 17 unrelated Italian patients with FOP, Bocciardi et al. (2009) identified heterozygosity for the R206H mutation in the ACVR1 gene. The authors noted that these patients showed extreme variability in severity of the disease. In a study of 112 patients with FOP, Kaplan et al. (2009) found that all 91 patients with classic FOP as well as 6 patients who had so-called 'FOP-plus' were heterozygous for the recurrent R206H mutation in the ACVR1 gene. In addition to having the classic defining features of FOP, patients who were designated 'FOP-plus' displayed atypical features, including polyostotic fibrous dysplasia (in a patient originally reported by Frame et al., 1972), thoracic insufficiency syndrome (in a patient previously studied by Kaplan and Glaser, 2005), aplastic anemia (in a patient previously described by Kaplan et al., 2007), craniopharyngioma, severe childhood glaucoma, and seizures. Using microarray analysis, Tanaka et al. (2012) found that expression of mutant ACVR1 with the R206H substitution in transfected mouse myoblasts significantly downregulated their expression of Ogn (602383), a secreted factor that enhanced differentiation of mouse osteoblasts in culture. Using reporter genes, Aykul et al. (2022) showed that monoclonal antibodies recognizing mouse and human ACVR1 inhibited ligand-induced signaling through both wildtype ACVR1 and ACVR1 with the R206H mutation in HEK293 cells in vitro. The same antibodies could block heterotopic ossification (HO) in mice with wildtype Acvr1, but they exacerbated HO in a mouse model of FOP with a knockin R206H mutation in Acvr1 by activating signaling of the Acvr1 mutant. The antibodies induced ligand-independent artificial dimerization of the Acvr1 R206H mutant to activate it and exacerbate HO in FOP mice, whereas wildtype Acvr1 was only activated in response to its ligands. The antibodies mimicked the effects of activin A and induced activation of Acvr1 R206H independently of activin A. However, antibody-induced activation of Acvr1 mutant was type II receptor dependent. The property of the ACVR1 R206H mutant to be activated when dimerized by anti-ACVR1 antibodies was conserved between mouse and human. (less)