MYH3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin

Autor: Julia Whittle, Lilian Antunes, Mya Harris, Zachary Upshaw, Diane S Sepich, Aaron N Johnson, Mayssa Mokalled, Lilianna Solnica‐Krezel, Matthew B Dobbs, Christina A Gurnett
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 12, Iss 11, Pp 1-14 (2020)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.202012356
Popis: Abstract 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.
Databáze: Directory of Open Access Journals
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