A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.
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.
Shore
Eileen M
EM
Center for Research in FOP and Related Disorders, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. shore@mail.med.upenn.edu
Xu
Meiqi
M
Feldman
George J
GJ
Fenstermacher
David A
DA
Cho
Tae-Joon
TJ
Choi
In Ho
IH
Connor
J Michael
JM
Delai
Patricia
P
Glaser
David L
DL
LeMerrer
Martine
M
Morhart
Rolf
R
Rogers
John G
JG
Smith
Roger
R
Triffitt
James T
JT
Urtizberea
J Andoni
JA
Zasloff
Michael
M
Brown
Matthew A
MA
Kaplan
Frederick S
FS
D030201:Activin Receptors, Type I / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002889:Chromosomes, Human, Pair 2; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009221:Myositis Ossificans / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D012333:RNA, Messenger; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I