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FB2026_01
,
released March 12, 2026
This report describes fibrodysplasia ossificans progressiva (FOP). FOP acts an autosomal dominant; most cases are sporadic. The human gene implicated in this disease is ACVR1 (Activin A Receptor Type 1), a component of the heteromeric activin receptor. There is a single orthologous gene in Drosophila, sax, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\sax is also orthologous to ACVRL1, which is implicated in telangiectasia, hereditary hemorrhagic, type 2 (MIM:600376).
Multiple UAS constructs of the human Hsap\ACVR1 gene have been introduced into flies, including wild-type and the pathological variant most frequently implicated in FOP.
Variant(s) implicated in human disease tested (as transgenic human gene, ACVR1): the R206H variant form has been introduced into flies. In Drosophila, this variant induces phenotypes indicative of constitutive hyperactive BMP signaling. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): K262H in the fly sax gene (corresponds to R206H in the human ACVR1 gene). Comparison of the K262H variant in the fly sax gene to the analogous variant in the introduced human gene reveals differences in phenotypes; the K262H variant exhibits hyperactive BMP signaling that appears to be as a result of heightened sensitivity to triggers, rather than as a result of constitutive activity.
Amorphic mutations of Dmel\sax are lethal in the larval or pupal stage. A variant implicated in human disease corresponds to a classical mutation in fly gene: G412E in the fly sax gene (designated sax2) corresponds to G356D in the human ACVR1 gene. The sax2 mutation is a gain-of-function allele; it has not been characterized in the context of an FOP disease model. Extensive genetic and physical interactions have been described for sax; see below and in the sax gene report.
[updated Sep. 2019 by FlyBase; FBrf0222196]
[FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; FOP](https://omim.org/entry/135100)
[ACTIVIN A RECEPTOR, TYPE I; ACVR1](https://omim.org/entry/102576)
FOP is an inherited connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification), such as the ligaments, tendons, and skeletal muscles. Specifically, this disorder causes the body's skeletal muscles and soft connective tissues to undergo a metamorphosis, essentially a transformation into bone, progressively locking joints in place and making movement difficult or impossible. [NORD, Fibrodysplasia Ossificans Progressiva; 2017.09.25]
Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an unpredictable episodic manner, with most patients being confined to a wheelchair by the third decade of life and requiring lifelong care (summary by Petrie et al., 2009; pubmed:19330033) [from MIM:135100; 2017.09.25]
FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference (summary by Petrie et al., 2009; pubmed:19330033). [from MIM:135100; 2017.09.25]
Fibrodysplasia ossificans progressiva (FOP) is caused by heterozygous mutation in the ACVR1 gene; most cases are sporadic. [from MIM:135100; 2017.09.25]
Caused by heterotopic ossification of skeletal muscles and soft connective tissues. [NORD, Fibrodysplasia Ossificans Progressiva; 2017.09.25]
ACVR1 encodes a Type I receptor for activin. Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I (I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling and type II receptors are required for binding ligands. [Gene Cards, ACVR1; 2017.09.25]
The most frequent ACVR1 variant associated with FOP (R206H), is located at the end of a highly conserved glycine-serine (GS) activation domain at the junction of the protein kinase domain; it is predicted to activate the ACVR1 protein and enhance receptor signaling (Shoe et al., 2006, 16642017; Kaplan et al, 2009, pubmed:19085907). [from MIM:135100, MIM:102576; 2017.09.25]
Many to one: 2 human to 1 Drosophila. The second human gene is ACVRL1.
High-scoring ortholog of human ACVR1; moderate-scoring ortholog of ACVRL1 (1 Drosophila to 2 human). Dmel\sax shares 50-53% identity and 65-66% similarity with the human genes.