Open AccessMYH 3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin
Author(s) -
Whittle Julia,
Antunes Lilian,
Harris Mya,
Upshaw Zachary,
Sepich Diane S,
Johnson Aaron N,
Mokalled Mayssa,
SolnicaKrezel Lilianna,
Dobbs Matthew B,
Gurnett Christina A
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012356
Subject(s) - zebrafish , notochord , arthrogryposis , biology , myosin , missense mutation , genetic model , genetics , mutation , endocrinology , microbiology and biotechnology , embryo , gene , embryogenesis
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 MYH 3 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 smyhc1 R673H/+ 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 smyhc1 R673H/R673H and transheterozygous smyhc1 R673H/− embryos exacerbated the notochord and muscle abnormalities, causing early lethality. Treatment of smyhc1 R673H/R673H embryos with the myosin ATP ase inhibitor, para‐aminoblebbistatin, which decreases actin–myosin affinity, normalized the notochord phenotype. Our zebrafish model of MYH 3 ‐associated DA 2A provides insight into pathogenic mechanisms and suggests a beneficial therapeutic role for myosin inhibitors in treating disabling contractures.