Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1.
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.
Kaplan
Frederick S
FS
Department of Orthopaedic Surgery, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6081, USA.
Xu
Meiqi
M
Seemann
Petra
P
Connor
J Michael
JM
Glaser
David L
DL
Carroll
Liam
L
Delai
Patricia
P
Fastnacht-Urban
Elisabeth
E
Forman
Stephen J
SJ
Gillessen-Kaesbach
Gabriele
G
Hoover-Fong
Julie
J
Köster
Bernhard
B
Pauli
Richard M
RM
Reardon
William
W
Zaidi
Syed-Adeel
SA
Zasloff
Michael
M
Morhart
Rolf
R
Mundlos
Stefan
S
Groppe
Jay
J
Shore
Eileen M
EM
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
C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I