MYH 3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin
J Whittle, L Antunes, M Harris, Z Upshaw… - EMBO molecular …, 2020 - embopress.org
J Whittle, L Antunes, M Harris, Z Upshaw, DS Sepich, AN Johnson, M Mokalled…
EMBO molecular medicine, 2020•embopress.orgDistal 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 …
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 …
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.
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