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Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1.
Hum Mutat. 2009 Mar; 30(3):379-90.HM

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+Show Affiliations

Department of Orthopaedic Surgery, University Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6081, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19085907

Citation

Kaplan, Frederick S., et al. "Classic and Atypical Fibrodysplasia Ossificans Progressiva (FOP) Phenotypes Are Caused By Mutations in the Bone Morphogenetic Protein (BMP) Type I Receptor ACVR1." Human Mutation, vol. 30, no. 3, 2009, pp. 379-90.
Kaplan FS, Xu M, Seemann P, et al. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009;30(3):379-90.
Kaplan, F. S., Xu, M., Seemann, P., Connor, J. M., Glaser, D. L., Carroll, L., Delai, P., Fastnacht-Urban, E., Forman, S. J., Gillessen-Kaesbach, G., Hoover-Fong, J., Köster, B., Pauli, R. M., Reardon, W., Zaidi, S. A., Zasloff, M., Morhart, R., Mundlos, S., Groppe, J., & Shore, E. M. (2009). Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Human Mutation, 30(3), 379-90. https://doi.org/10.1002/humu.20868
Kaplan FS, et al. Classic and Atypical Fibrodysplasia Ossificans Progressiva (FOP) Phenotypes Are Caused By Mutations in the Bone Morphogenetic Protein (BMP) Type I Receptor ACVR1. Hum Mutat. 2009;30(3):379-90. PubMed PMID: 19085907.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. AU - Kaplan,Frederick S, AU - Xu,Meiqi, AU - Seemann,Petra, AU - Connor,J Michael, AU - Glaser,David L, AU - Carroll,Liam, AU - Delai,Patricia, AU - Fastnacht-Urban,Elisabeth, AU - Forman,Stephen J, AU - Gillessen-Kaesbach,Gabriele, AU - Hoover-Fong,Julie, AU - Köster,Bernhard, AU - Pauli,Richard M, AU - Reardon,William, AU - Zaidi,Syed-Adeel, AU - Zasloff,Michael, AU - Morhart,Rolf, AU - Mundlos,Stefan, AU - Groppe,Jay, AU - Shore,Eileen M, PY - 2008/12/17/entrez PY - 2008/12/17/pubmed PY - 2009/5/29/medline SP - 379 EP - 90 JF - Human mutation JO - Hum Mutat VL - 30 IS - 3 N2 - 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. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/19085907/Classic_and_atypical_fibrodysplasia_ossificans_progressiva__FOP__phenotypes_are_caused_by_mutations_in_the_bone_morphogenetic_protein__BMP__type_I_receptor_ACVR1_ L2 - https://doi.org/10.1002/humu.20868 DB - PRIME DP - Unbound Medicine ER -