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ZFIN ID: ZDB-PUB-201006-8
MYH3-associated distal arthrogryposis zebrafish model is normalized with para-aminoblebbistatin
Whittle, J., Antunes, L., Harris, M., Upshaw, Z., Sepich, D.S., Johnson, A.N., Mokalled, M., Solnica-Krezel, L., Dobbs, M.B., Gurnett, C.A.
Date: 2020
Source: EMBO Molecular Medicine   12(11): e12356 (Journal)
Registered Authors: Gurnett, Christina, Mokalled, Mayssa, Sepich, Diane, Solnica-Krezel, Lilianna, Whittle, Julia
Keywords: contracture, hypercontractile, muscle, myosin, notochord
MeSH Terms:
  • Animals
  • Arthrogryposis*/genetics
  • Humans
  • Mutation
  • Phenotype
  • Synostosis*
  • Zebrafish
PubMed: 33016623 Full text @ EMBO Mol. Med.
Distal arthrogryposis (DA) is group of syndromes characterized by congenital joint contractures. Treatment development is hindered by the lack of vertebrate models. Here, we describe a zebrafish model in which a common MYH3 missense mutation (R672H) was introduced into the orthologous zebrafish gene smyhc1 (slow myosin heavy chain 1) (R673H). We simultaneously created a smyhc1 null allele (smyhc1- ), which allowed us to compare the effects of both mutant alleles on muscle and bone development, and model the closely related disorder, spondylocarpotarsal synostosis syndrome. Heterozygous smyhc1R673H/+ embryos developed notochord kinks that progressed to scoliosis with vertebral fusions; motor deficits accompanied the disorganized and shortened slow-twitch skeletal muscle myofibers. Increased dosage of the mutant allele in both homozygous smyhc1R673H/R673H and transheterozygous smyhc1R673H/- embryos exacerbated the notochord and muscle abnormalities, causing early lethality. Treatment of smyhc1R673H/R673H embryos with the myosin ATPase inhibitor, para-aminoblebbistatin, which decreases actin-myosin affinity, normalized the notochord phenotype. Our zebrafish model of MYH3-associated DA2A provides insight into pathogenic mechanisms and suggests a beneficial therapeutic role for myosin inhibitors in treating disabling contractures.