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Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish.
Bone. 2018 04; 109:225-231.BONE

Abstract

The large majority of cases of the autosomal dominant human disease fibrodysplasia ossificans progressiva (FOP) are caused by gain-of-function Arg206His mutations in the BMP type I receptor ACVR1 (ALK2). The Arg206His mutation is located in the GS domain of the type I receptor. This region is normally phosphorylated by the BMP type II receptor, which activates the type I receptor to phosphorylate its substrate, the signal transducer Smad1/5/8. A small subset of patients with FOP carry variant mutations in ACVR1 altering Gly328 to Trp, Glu or Arg. Since these mutations lie outside the GS domain, the mechanism through which ACVR1 Gly328 mutations cause disease remains unclear. We used a zebrafish embryonic development assay to test the signaling of human ACVR1 Gly328 mutant receptors comparing them to the Arg206His mutant. In this assay increased or decreased BMP pathway activation alters dorsal-ventral axial patterning, providing a sensitive assay for altered BMP signaling levels. We expressed the human ACVR1 Gly328 mutant receptors in zebrafish embryos to investigate their signaling activities. We found that all ACVR1 Gly328 human mutations ventralized wild-type embryos and could partially rescue Bmp7-deficient embryos, indicating that these mutant receptors can activate BMP signaling in a BMP ligand-independent manner. The degree of ventralization or rescue was similar among all three Gly328 mutants. Smad1/5 phosphorylation, a readout of BMP receptor signaling, was mildly increased by ACVR1 Gly328 mutations. Gene expression analyses demonstrate expanded ventral and reciprocal loss of dorsal cell fate markers. This study demonstrates that Gly328 mutants increase receptor activation and BMP ligand-independent signaling through Smad phosphorylation.

Authors+Show Affiliations

Division of Human Genetics and Molecular Biology, and Division of Biochemical Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Universite de Montreal, Montreal, QC, Canada.Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.Department of Orthopedic Surgery, and the Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, and the Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: mullins@pennmedicine.upenn.edu.

Pub Type(s)

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

Language

eng

PubMed ID

29307777

Citation

Mucha, Bettina E., et al. "Variant BMP Receptor Mutations Causing Fibrodysplasia Ossificans Progressiva (FOP) in Humans Show BMP Ligand-independent Receptor Activation in Zebrafish." Bone, vol. 109, 2018, pp. 225-231.
Mucha BE, Hashiguchi M, Zinski J, et al. Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish. Bone. 2018;109:225-231.
Mucha, B. E., Hashiguchi, M., Zinski, J., Shore, E. M., & Mullins, M. C. (2018). Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish. Bone, 109, 225-231. https://doi.org/10.1016/j.bone.2018.01.002
Mucha BE, et al. Variant BMP Receptor Mutations Causing Fibrodysplasia Ossificans Progressiva (FOP) in Humans Show BMP Ligand-independent Receptor Activation in Zebrafish. Bone. 2018;109:225-231. PubMed PMID: 29307777.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish. AU - Mucha,Bettina E, AU - Hashiguchi,Megumi, AU - Zinski,Joseph, AU - Shore,Eileen M, AU - Mullins,Mary C, Y1 - 2018/01/04/ PY - 2017/09/14/received PY - 2017/12/23/revised PY - 2018/01/03/accepted PY - 2018/1/9/pubmed PY - 2018/11/20/medline PY - 2018/1/9/entrez KW - ACVR1 KW - BMP signaling KW - Dorsal-ventral embryonic patterning KW - FOP KW - Smad1/5 KW - Zebrafish SP - 225 EP - 231 JF - Bone JO - Bone VL - 109 N2 - The large majority of cases of the autosomal dominant human disease fibrodysplasia ossificans progressiva (FOP) are caused by gain-of-function Arg206His mutations in the BMP type I receptor ACVR1 (ALK2). The Arg206His mutation is located in the GS domain of the type I receptor. This region is normally phosphorylated by the BMP type II receptor, which activates the type I receptor to phosphorylate its substrate, the signal transducer Smad1/5/8. A small subset of patients with FOP carry variant mutations in ACVR1 altering Gly328 to Trp, Glu or Arg. Since these mutations lie outside the GS domain, the mechanism through which ACVR1 Gly328 mutations cause disease remains unclear. We used a zebrafish embryonic development assay to test the signaling of human ACVR1 Gly328 mutant receptors comparing them to the Arg206His mutant. In this assay increased or decreased BMP pathway activation alters dorsal-ventral axial patterning, providing a sensitive assay for altered BMP signaling levels. We expressed the human ACVR1 Gly328 mutant receptors in zebrafish embryos to investigate their signaling activities. We found that all ACVR1 Gly328 human mutations ventralized wild-type embryos and could partially rescue Bmp7-deficient embryos, indicating that these mutant receptors can activate BMP signaling in a BMP ligand-independent manner. The degree of ventralization or rescue was similar among all three Gly328 mutants. Smad1/5 phosphorylation, a readout of BMP receptor signaling, was mildly increased by ACVR1 Gly328 mutations. Gene expression analyses demonstrate expanded ventral and reciprocal loss of dorsal cell fate markers. This study demonstrates that Gly328 mutants increase receptor activation and BMP ligand-independent signaling through Smad phosphorylation. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/29307777/Variant_BMP_receptor_mutations_causing_fibrodysplasia_ossificans_progressiva__FOP__in_humans_show_BMP_ligand_independent_receptor_activation_in_zebrafish_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(18)30002-4 DB - PRIME DP - Unbound Medicine ER -