title: Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1.
abstract: Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant human disorder of bone formation that causes developmental skeletal defects and extensive debilitating bone formation within soft connective tissues (heterotopic ossification) during childhood. All patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G>A; p.R206H) in the glycine and serine residue (GS) activation domain of activin A type I receptor/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. Among patients with FOP-like heterotopic ossification and/or toe malformations, we identified patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP-plus (classic defining features of FOP plus one or more atypical features) and FOP variants (major variations in one or both of the two classic defining features of FOP). All patients examined have heterozygous ACVR1 missense mutations in conserved amino acids. While the recurrent c.617G>A; p.R206H mutation was found in all cases of classic FOP and most cases of FOP-plus, novel ACVR1 mutations occur in the FOP variants and two cases of FOP-plus. Protein structure homology modeling predicts that each of the amino acid substitutions activates the ACVR1 protein to enhance receptor signaling. We observed genotype-phenotype correlation between some ACVR1 mutations and the age of onset of heterotopic ossification or on embryonic skeletal development.
authors.affiliation: Department of Orthopaedic Surgery, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6081, USA.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.forename: Meiqi
authors.initials: M
authors.lastname: Xu
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
authors.forename: J Michael
authors.initials: JM
authors.lastname: Connor
authors.forename: David L
authors.initials: DL
authors.lastname: Glaser
authors.forename: Liam
authors.initials: L
authors.lastname: Carroll
authors.forename: Patricia
authors.initials: P
authors.lastname: Delai
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Fastnacht-Urban
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Julie
authors.initials: J
authors.lastname: Hoover-Fong
authors.forename: Bernhard
authors.initials: B
authors.lastname: Köster
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pauli
authors.forename: William
authors.initials: W
authors.lastname: Reardon
authors.forename: Syed-Adeel
authors.initials: SA
authors.lastname: Zaidi
authors.forename: Michael
authors.initials: M
authors.lastname: Zasloff
authors.forename: Rolf
authors.initials: R
authors.lastname: Morhart
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Jay
authors.initials: J
authors.lastname: Groppe
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
mesh_terms: D030201:Activin Receptors, Type I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009221:Myositis Ossificans / Q000235:genetics* / Q000473:pathology; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I