A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.

BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment

“…The first is a rare congenital disorder with a frequency of 1 per 2 million (2) that is caused by a recently discovered recurrent missense mutation in the BMP type 1 receptor activin receptor 1A/activin-like kinase-2 (ACVR1/ALK2). (3) Sporadic mutations and an autosomal dominant pattern of inheritance are responsible for the disease, in which ossification can occur with or without injury and typically grows in a predictable pattern. (3) The second and by far most common type of traumatic HO occurs in injured tissues, notably at sites of damaged muscle.…”

“…(3) Sporadic mutations and an autosomal dominant pattern of inheritance are responsible for the disease, in which ossification can occur with or without injury and typically grows in a predictable pattern. (3) The second and by far most common type of traumatic HO occurs in injured tissues, notably at sites of damaged muscle. (4) Many traumatic conditions have been associated with traumatic HO, including fractures, burns, immobilization, total hip replacement surgeries, and spinal cord and brain injuries.…”

Disease-causing allele-specific silencing against the ALK2 mutants, R206H and G356D, in fibrodysplasia ossificans progressiva

“…1,2 The activin receptor type IA/ activin-like kinase 2 (ACVR1/ALK2) gene has been identified as the gene responsible for FOP, 3 and a recurrent mutation, 617G4A(R206H), has been found in both familial and sporadic FOP cases of various ethnic groups. 3 In addition, other types of heterozygous ALK2 mutations have been also detected in patients with atypical FOP, for example, 1067G4A(G356D).…”

“…1,2 The activin receptor type IA/ activin-like kinase 2 (ACVR1/ALK2) gene has been identified as the gene responsible for FOP, 3 and a recurrent mutation, 617G4A(R206H), has been found in both familial and sporadic FOP cases of various ethnic groups. 3 In addition, other types of heterozygous ALK2 mutations have been also detected in patients with atypical FOP, for example, 1067G4A(G356D). 1,2,4 The pathogenic, mutant ALK2 receptor appears to be a highly sensitive bone morphogenetic protein (BMP) type I receptor to BMPs and external triggers, resulting in an apparently constitutively active ALK2 receptor, and thereby readily inducing heterotopic bone formation in FOP.…”

Evolution of the radiographic appearance of the metaphyses over the first year of life in type V osteogenesis imperfecta: Clues to pathogenesis

“…The transforming growth factor b (TGF-b) superfamily signaling pathways are one source of candidate molecules, including activin, other bone morphogenetic proteins, TGF-b isoforms, and all their respective receptors. Members of this superfamily have been implicated in diverse skeletal disorders such as fibrodysplasia ossificans progressive, (3) Camurati-Engelmann disease, (4) and acromesomelic chondrodysplasia, HunterThompson type. (5) The control of growth plate development is complex and under the influence of numerous interacting molecules.…”