PUBLICATION

Functional comparison of human ACVR1 and zebrafish Acvr1l FOP-associated variants in embryonic zebrafish

Authors
Lalonde, R.L., Nicolas, H.A., Cutler, R.S., Pantekidis, I., Zhang, W., Yelick, P.C.
ID
ZDB-PUB-230107-1
Date
2023
Source
Developmental Dynamics : an official publication of the American Association of Anatomists   252(5): 605-628 (Journal)
Registered Authors
Yelick, Pamela C.
Keywords
none
MeSH Terms
  • Activin Receptors, Type I*/genetics
  • Animals
  • Embryo, Nonmammalian*/metabolism
  • Humans
  • Mutation
  • Myositis Ossificans*
  • Ossification, Heterotopic*
  • Signal Transduction
  • Zebrafish
(all 9)
PubMed
36606464 Full text @ Dev. Dyn.
Abstract
Background Fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by progressive heterotopic ossification of muscle and connective tissues, is caused by autosomal dominant activating mutations in the type I receptor, ACVR1/ALK2. The classic human FOP variant, ACVR1R206H , shows increased BMP signaling and activation by Activins.
Results Here we performed in vivo functional characterization of human ACVR1R206H and orthologous zebrafish Acvr1lR203H using early embryonic zebrafish dorsoventral patterning as a phenotypic readout for receptor activity. Our results showed that human ACVR1R206H and zebrafish Acvr1lR203H exhibit functional differences in early embryonic zebrafish, and that human ACVR1R206H retained its signaling activity in the absence of a ligand-binding domain (LBD). We also showed, for the first time, that zebrafish Acvr2ba/Acvr2bb receptors are required for human ACVR1R206H signaling in early embryonic zebrafish.
Conclusions Together, these data provide new insight into ACVR1R206H signaling pathways that may facilitate the design of new and effective therapies for FOP patients. This article is protected by copyright. All rights reserved.
Genes / Markers
Marker Marker Type Name
acvr1lGENEactivin A receptor, type 1 like
acvr2aaGENEactivin A receptor type 2Aa
acvr2abGENEactivin A receptor type 2Ab
acvr2baGENEactivin A receptor type 2Ba
acvr2bbGENEactivin A receptor type 2Bb
acvrl1GENEactivin A receptor like type 1
bmpr2aGENEbone morphogenetic protein receptor, type II a (serine/threonine kinase)
bmpr2bGENEbone morphogenetic protein receptor, type II b (serine/threonine kinase)
hsp70lGENEheat shock cognate 70-kd protein, like
1 - 9 of 9
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Figures
No images available
Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
tm110b
    		Point Mutation
    zf3850TgTransgenic Insertion
      zf3991TgTransgenic Insertion
        zf3992TgTransgenic Insertion
          zf3993
            		Small Deletion
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            acvr1lCRISPR3-acvr1lCRISPR
            acvr1lCRISPR4-acvr1lCRISPR
            acvr2aaMO2-acvr2aaMRPHLNO
            acvr2abMO1-acvr2abMRPHLNO
            acvr2baMO2-acvr2baMRPHLNO
            acvr2bbMO1-acvr2bbMRPHLNO
            bmpr2aMO2-bmpr2aMRPHLNO
            bmpr2bMO2-bmpr2bMRPHLNO
            1 - 8 of 8
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            Fish
            Antibodies
            Orthology
            Engineered Foreign Genes
            Marker Marker Type Name
            mCherryEFGmCherry
            1 - 1 of 1
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            Mapping
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            Citation
            Lalonde, R.L., Nicolas, H.A., Cutler, R.S., Pantekidis, I., Zhang, W., Yelick, P.C. (2023) Functional comparison of human ACVR1 and zebrafish Acvr1l FOP-associated variants in embryonic zebrafish. Developmental Dynamics : an official publication of the American Association of Anatomists. 252(5):605-628.