Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1

Frederick S. Kaplan, Meiqi Xu, Petra Seemann, J. Michael Connor, David L. Glaser, Liam Carroll, Patricia Delai, Elisabeth Fastnacht-Urban, Stephen J. Forman, Gabriele Gillessen-Kaesbach, Julie Hoover-Fong, Bernhard Köster, Richard M. Pauli, William Reardon, Syed Adeel Zaidi, Michael Zasloff, Rolf Morhart, Stefan Mundlos, Jay Groppe, Eileen M. Shore

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)379-390
Number of pages12
JournalHuman mutation
Volume30
Issue number3
DOIs
StatePublished - Mar 2009

Keywords

  • ACVR1
  • ALK2
  • BMP type I receptor
  • Bone morphogenetic protein
  • Clinical variants
  • FOP
  • Fibrodysplasia ossificans progressiva
  • Heterotopic ossification

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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