Alternative titles; symbols
HGNC Approved Gene Symbol: ACVR1
SNOMEDCT: 82725007; ICD10CM: M61.1, M61.10; ICD9CM: 728.11;
Cytogenetic location: 2q24.1 Genomic coordinates (GRCh38): 2:157,736,446-157,876,330 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q24.1 | Fibrodysplasia ossificans progressiva | 135100 | Autosomal dominant | 3 |
Activins are members of a family of polypeptide growth factors that also includes also the transforming growth factors-beta (190180, 190220, 190230), mullerian duct-inhibiting substance, and several bone morphogenetic proteins. Although activins were discovered by virtue of their capacity to stimulate the production of follicle-stimulating hormone (FSH; 136530) by the pituitary gland and inhibins were initially characterized as FSH inhibitors, activins and inhibins are dimeric proteins that share a common subunit. There are 3 activins (A, B, and A-B), comprising different combinations of 2 closely related beta subunits (beta-A/beta-A; beta-B/beta-B; and beta-A/beta-B, respectively) and 2 inhibins (A and B), consisting of 1 beta-subunit and an inhibin-specific alpha subunit (alpha/beta-A and alpha/beta-B). Activins impinge on a much broader spectrum of cells than do inhibins; however, in those systems in which both proteins are functional, they have opposing biologic effects (summary by Mathews and Vale, 1991).
Mathews and Vale (1991) cloned an activin receptor cDNA by use of a method that has been used to clone other receptors, such as that for erythropoietin. The cloning was based on the ability of the receptor to bind a labeled ligand following expression of a cDNA library in mammalian cells. The cDNA coded for a protein of 494 amino acids comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. On the basis of affinity-crosslinking studies, Mathews and Vale (1991) identified 2 types of activin receptors. The type I receptor has a molecular size of 65 kD, while the molecular size of the type II receptor (see 102581) is 85 kD.
Human cDNA clones encoding 4 putative transmembrane ser/thr kinases were identified by ten Dijke et al. (1993). Using degenerate DNA primers based on the human activin receptor type II and C. elegans Daf-1 gene products, they PCR-amplified mRNA from human erythroleukemia (HEL) cells, a cell type known to respond both to activin (147290) and TGF-beta (190180). The ALK2 gene encodes a 509-amino acid polypeptide that shares similar sequence and domain structures with the other 3 ALK genes they cloned. ALK1 (ACVRL1; 601284), ALK2, ALK3 (601299), and ALK4 (601300) share approximately 40% sequence identity with activin receptors type II and IIB, TGF-beta receptor (see 190181), and Daf-1 in their kinase domains but share 60 to 79% sequence identity among themselves, suggesting to ten Dijke et al. (1993) that the ALK gene products form a subfamily of receptor ser/thr kinases. By Northern analysis, ten Dijke et al. (1993) showed that ALK2 is expressed most strongly in placenta, skeletal muscle, and heart and to a lesser extent in kidney, brain, and lung. Matsuzaki et al. (1993) and Attisano et al. (1993) also cloned a human cDNA encoding ACVRLK2. Matsuzaki et al. (1993) termed the gene 'serine/threonine kinase receptor' (SKR1) and presented data on its wide tissue expression distribution. By transient transfection of COS cells and subsequent binding assays, Matsuzaki et al. (1993) found that activin, TGF-beta 1, and BMP-2B (112262) do not bind SKR1. Attisano et al. (1993) further characterized the gene product and concluded that its protein product (termed ActR1 by them) is an activin type I receptor. They found that ActR1, but not ACVRL1, signals a particular transcriptional response in concert with activin type II receptors.
By Southern blot analysis of DNAs from a somatic cell hybrid mapping panel, Roijer et al. (1998) mapped the ACVR1 gene to chromosome 2. By fluorescence in situ hybridization, they regionalized the gene to chromosome 2q23-q24.
By sequence analysis of all ACVR1 protein-coding exons and splice junctions, Shore et al. (2006) identified a heterozygous mutation (R206H; 102576.0001) in all affected members examined from families with fibrodysplasia ossificans progressiva (FOP; 135100), including all 5 families used for linkage analysis, and in all of 32 sporadic FOP patients with unambiguous clinical features studied. The examined individuals with the R206H mutation included an individual with a previously reported, but unverifiable, mutation in the noggin gene (NOG; 602991).
In a 62-year-old Japanese man with slowly progressive FOP, Furuya et al. (2008) identified heterozygosity for a mutation (G356D; 102576.0002) in the ACVR1 gene. The authors suggested that the patient's longevity and slow progression of respiratory difficulties might be related to the position of the G356D mutation in the protein kinase domain rather than in the functionally important glycine/serine-rich domain where the common R206H mutation is located.
Bocciardi et al. (2009) analyzed exon 4 of the ACVR1 gene in 17 unrelated Italian patients with FOP and identified heterozygosity for the recurrent R206H mutation in 15 patients. In the remaining 2 patients, they sequenced the complete ACVR1 gene and identified heterozygosity for the same mutation in both (R258S; 102576.0003).
Kaplan et al. (2009) studied 112 FOP patients, including 21 cases of atypical FOP, which formed 2 classes: so-called 'FOP-plus,' in which patients had the classic defining features of FOP plus 1 or more atypical features; and 'FOP variants,' in which there were major variations in 1 or both of the 2 classic defining features of FOP. The recurrent ACVR1 mutation R206H was found in all of the patients with classic FOP and most of those with FOP-plus, whereas the G356D mutation or novel ACVR1 mutations were identified in patients with FOP variants and in 2 cases of FOP-plus (see, e.g., 102576.0004-102576.0007). Kaplan et al. (2009) noted that all mutations in ACVR1 associated with FOP in any form were located in or adjacent to the GS regulatory region or active site of the kinase, and all were predicted by protein structure homology modeling to activate the ACVR1 protein and enhance receptor signaling.
In a 20-year-old woman with FOP, who had a later onset and relatively mild course of disease, Petrie et al. (2009) identified heterozygosity for an R202I mutation in the ACVR1 gene (102576.0008). In a 52-year-old woman with FOP, who was born with severe reduction deformities of all digits, they identified a heterozygous G328E mutation (102576.0006).
In a female patient with variant FOP, who had normal great toes and late-onset heterotopic ossification and was misdiagnosed with ankylosing spondylitis for several years, Barnett et al. (2011) identified heterozygosity for the R202I mutation in the ACVR1 gene.
For discussion of a possible association between variation in the ACVR1 gene and atrioventricular septal defects, see AVSD1 (606215).
Yu et al. (2008) induced postnatal overexpression of constitutively active Q207D-mutant Alk2 in the left hindlimbs of mice and observed development of ectopic endochondral bone formation, joint fusion, and functional impairment, thus phenocopying key aspects of human FOP. Administration of a selective inhibitor of BMP type I receptor kinases inhibited activation of the BMP signaling effectors SMAD1 (601595), SMAD5 (603110), and SMAD8 (603295) in tissues expressing the mutant Alk2 and reduced ectopic ossification and functional impairment. Global postnatal expression of the Q207D-mutant Alk2 did not lead to ectopic ossification; however, in combination with infection by a control adenovirus, ectopic bone formation was induced. Corticosteroid treatment inhibited ossification, suggesting that expression of mutant Alk2 and an inflammatory milieu are both required for development of ectopic ossification in this model. Yu et al. (2008) suggested that dysregulated ALK2 kinase activity plays a role in the pathogenesis of FOP.
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.
In a 62-year-old Japanese man with slowly progressive fibrodysplasia ossificans progressiva (FOP; 135100), Furuya et al. (2008) identified heterozygosity for a de novo 1097G-A transition in exon 7 of the ACVR1 gene, resulting in a gly356-to-asp (G356D) substitution at a conserved residue in the protein kinase domain. The mutation was not found in his 2 unaffected sibs or in 150 controls.
Kaplan et al. (2009) identified the G356D mutation in the ACVR1 gene in 1 patient with so-called 'FOP-plus' and in 3 patients with 'variant FOP.' The patient with FOP-plus had persistence of primary teeth into adulthood and primary amenorrhea in addition to the classic defining features of FOP. One of the 3 patients with variant FOP had the characteristic malformation of the great toes, although it was asymmetric, whereas the other 2 had bilateral absence of or severe reduction deficit of the great toes and thumbs.
In 2 Italian patients with fibrodysplasia ossificans progressiva (FOP; 135100), Bocciardi et al. (2009) identified heterozygosity for a 774G-C transversion in the ACVR1 gene, resulting in an arg258-to-ser (R258S) substitution at a highly conserved residue in the kinase domain. The mutation was not found in the unaffected parents of 1 of the patients or in 104 controls. One of the patients with the R258S mutation displayed an FOP variant phenotype, with typical anatomic distribution of progressive heterotopic ossification but absence of the great toe malformation; the other patient had the great toe malformation, but to a 'rather mild' degree.
In 2 probands with fibrodysplasia ossificans progressiva (FOP; 135100) who had major variations in 1 or both of the classic defining features of FOP, Kaplan et al. (2009) identified heterozygosity for a 982G-A transition in the ACVR1 gene, resulting in a gly328-to-arg (G328R) substitution in the protein kinase domain. One of the probands was from a family previously reported by Virdi et al. (1999), in which a mother and 2 daughters had a mild FOP phenotype with either normal or minimally affected toes and no or late onset of heterotopic ossification. Kaplan et al. (2009) stated that no substantial progression of FOP had occurred in the mother or daughters since the previous report. The mutation was found in all 3 affected family members, but not in the unaffected father or maternal grandmother. The second proband had normal toes but short thumbs, and did not develop heterotopic ossification until 26 years of age; in addition, CT scan of the head and neck showed a hypoplastic cerebellum.
In 2 female probands with fibrodysplasia ossificans progressiva (FOP; 135100) who had major variations in 1 or both of the classic defining features of FOP, Kaplan et al. (2009) identified heterozygosity for a 982G-T transversion in the ACVR1 gene, resulting in a gly328-to-trp (G328W) substitution in the protein kinase domain. Both probands had severe reduction deficits of the great toes, with absent toenails in the affected digits, and malformed or reduction deficits of the thumbs. Both developed sparse scalp hair in the second decade of life and had mild cognitive impairment without attention deficit. One of the patients had cerebellar abnormalities noted on CT scan, without associated impairment in movement. The other patient, who had previously been reported by Connor and Evans (1982), developed progressive heterotopic ossification in the characteristic anatomic patterns at 8 years of age, and also had mild conductive hearing impairment and short broad femoral necks.
In 2 female probands with fibrodysplasia ossificans progressiva (FOP; 135100) who had major variations in 1 or both of the classic defining features of FOP, Kaplan et al. (2009) identified heterozygosity for a 983G-A transition in the ACVR1 gene, resulting in a gly328-to-glu (G328E) substitution in the protein kinase domain. The patients, 1 of whom had previously been described by Connor and Evans (1982), had severe reduction deficits of the great toes and thumbs at birth, with absent toenails in the affected digits. Both developed sparse scalp hair in the second decade of life and had mild cognitive impairment without attention deficit.
In a 52-year-old woman from the UK with fibrodysplasia ossificans progressiva, originally reported by Smith et al. (1976) and restudied by Connor and Evans (1982), Petrie et al. (2009) identified heterozygosity for a G328E mutation in exon 8 of the ACVR1 gene that was not found in 100 controls. Severe reduction deformities had been noted in all of the patient's digits at birth, and the disease presented as painful lumps on the occiput. By 6 years of age, she had a stiff spine and shoulders; by age 14 years, both elbows and the right hip showed ectopic ossification and she also developed diffuse scalp hair thinning. At 26 years of age, the patient had complete spinal fixation, the shoulders were fixed in adduction, elbows fixed in flexion, hip movement restricted and fixed in slight flexion, and jaw gape was 0.3 cm. She had mild cognitive impairment.
In a female proband with fibrodysplasia ossificans progressiva (FOP; 135100) who had major variations in 1 or both of the classic defining features of FOP, Kaplan et al. (2009) identified heterozygosity for a 1124G-C transversion in the ACVR1 gene, resulting in an arg375-to-pro (R375P) substitution in the protein kinase domain. The patient had clinically and radiographically normal toes. FOP flare-ups began at 14 years of age and progression of the disease was slow and evanescent. At 40 years of age, she had limited motion of the cervical spine and shoulders with heterotopic ossification in the neck, back, and right hip, but was still ambulatory.
In a female patient with fibrodysplasia ossificans progressiva (FOP; 135100), Petrie et al. (2009) identified heterozygosity for a 605G-T transversion in exon 6 of the ACVR1 gene, resulting in an arg202-to-ile (R202I) substitution in the GS domain that was not found in 100 controls. The patient was diagnosed at age 14 years when she developed a painful bony lump over her right scapula after a fall and subsequently developed multiple tender bony swellings; the diagnosis was confirmed upon observation of a unilateral short great toe (her other great toe was normal). Her right shoulder was fixed in internal rotation, with fixed flexion deformities of both elbows and restriction of movements of the lumbar spine. She had frequent flare-ups of the condition with inflammatory lesions over the shoulder joints and neck and jaw, and developed fusion of the neck within 6 months of clinical presentation. Petrie et al. (2009) noted that although the R202I mutation occurs within the same ACVR1 domain as the recurrent R206H mutation (102576.0001), this patient's disease had a relatively late age of onset and was less severe than that of a typical FOP patient; the authors also stated that unilateral malformation of the great toe had not previously been documented in an FOP patient.
In a female patient with variant FOP, who had normal great toes and late-onset heterotopic ossification and was misdiagnosed with ankylosing spondylitis for several years, Barnett et al. (2011) identified heterozygosity for the R202I mutation in the ACVR1 gene.
In a 45-year-old woman with a late-onset, mild form of fibrodysplasia ossificans progressiva (FOP; 135100), Gregson et al. (2011) identified heterozygosity for a c.587T-C transition in exon 6 of the ACVR1 gene, resulting in a leu196-to-pro (L196P) substitution. The mutation was not found in 100 healthy controls. The patient, who had normal toes and bilateral mild camptodactyly of the fifth fingers, was 21 years old when she developed heterotopic ossification following a car accident. Asymptomatic early ossification of cervical spine facet joints was noted at age 42, and she also experienced recurrent episodes of inflammation without subsequent ossification. Gregson et al. (2011) stated that this patient had the most benign clinical course of any reported FOP case.
Ohte et al. (2011) studied the biologic activity of the ACVR1 L196P mutant in vitro and found that overexpression of L196P mutant protein induced BMP (see 112264)-specific activities, including the suppression of myogenesis and induction of alkaline phosphatase activity, as well as increasing BMP-specific luciferase reporter activity and increasing phosphorylation of SMAD1 (601595)/5 (603110). These activities of the L196P mutant were higher than those of the G356D ACVR1 mutant (102576.0002) and the equivalent of the recurrent R206H mutant (102576.0001). In addition, L196P was equally or more resistant to inhibitors compared to R206H. Ohte et al. (2011) suggested that L196P activity might be suppressed by a novel mechanism in the mildly affected patient reported by Gregson et al. (2011).
In a 22-year-old Japanese man who exhibited delayed onset and a slower, milder course of FOP, Nakahara et al. (2014) identified heterozygosity for the L196P mutation in ACVR1. The patient first developed heterotopic ossification after a fall from a height of 1 to 2 meters at 17 years of age, and examination at age 22 revealed limited range of motion of cervical and lumbar spine and at the hip joints. He had camptodactyly of the left fifth digit, short toes, and absence of the distal interphalangeal joint of the fourth and fifth toes bilaterally. X-rays showed mature heterotopic calcification bilaterally in the lumbar paraspinal muscles, mild osteosclerotic lesions bilaterally in the inner cortex of the proximal tibia, and slight enlargement of the C6 spinous process with narrowing of the C6-7 intervertebral joint.
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