Cargando…
MYH3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin
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...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645368/ https://www.ncbi.nlm.nih.gov/pubmed/33016623 http://dx.doi.org/10.15252/emmm.202012356 |
_version_ | 1783606642068160512 |
---|---|
author | Whittle, Julia Antunes, Lilian Harris, Mya Upshaw, Zachary Sepich, Diane S Johnson, Aaron N Mokalled, Mayssa Solnica‐Krezel, Lilianna Dobbs, Matthew B Gurnett, Christina A |
author_facet | Whittle, Julia Antunes, Lilian Harris, Mya Upshaw, Zachary Sepich, Diane S Johnson, Aaron N Mokalled, Mayssa Solnica‐Krezel, Lilianna Dobbs, Matthew B Gurnett, Christina A |
author_sort | Whittle, Julia |
collection | PubMed |
description | 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 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 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. |
format | Online Article Text |
id | pubmed-7645368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-76453682020-11-13 MYH3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin Whittle, Julia Antunes, Lilian Harris, Mya Upshaw, Zachary Sepich, Diane S Johnson, Aaron N Mokalled, Mayssa Solnica‐Krezel, Lilianna Dobbs, Matthew B Gurnett, Christina A EMBO Mol Med Articles 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 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 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. John Wiley and Sons Inc. 2020-10-05 2020-11-06 /pmc/articles/PMC7645368/ /pubmed/33016623 http://dx.doi.org/10.15252/emmm.202012356 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Whittle, Julia Antunes, Lilian Harris, Mya Upshaw, Zachary Sepich, Diane S Johnson, Aaron N Mokalled, Mayssa Solnica‐Krezel, Lilianna Dobbs, Matthew B Gurnett, Christina A MYH3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin |
title |
MYH3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin |
title_full |
MYH3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin |
title_fullStr |
MYH3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin |
title_full_unstemmed |
MYH3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin |
title_short |
MYH3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin |
title_sort | myh3‐associated distal arthrogryposis zebrafish model is normalized with para‐aminoblebbistatin |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645368/ https://www.ncbi.nlm.nih.gov/pubmed/33016623 http://dx.doi.org/10.15252/emmm.202012356 |
work_keys_str_mv | AT whittlejulia myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin AT antuneslilian myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin AT harrismya myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin AT upshawzachary myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin AT sepichdianes myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin AT johnsonaaronn myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin AT mokalledmayssa myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin AT solnicakrezellilianna myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin AT dobbsmatthewb myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin AT gurnettchristinaa myh3associateddistalarthrogryposiszebrafishmodelisnormalizedwithparaaminoblebbistatin |