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 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.
Highlights
Distal arthrogryposis (DA) describes a group of congenital musculoskeletal syndromes characterized by contractures in the joints of the hands and feet
By showing that the smyhc1R673H zebrafish model replicates key aspects of the congenital disorder that can be normalized with myosin inhibitors, we have demonstrated its value for evaluating therapeutics for use in human DA patients
Understanding the functional consequences of MYH3 variants associated with human disease has been limited by the lack of access to human skeletal muscle tissue during embryonic development
Summary
Distal arthrogryposis (DA) describes a group of congenital musculoskeletal syndromes characterized by contractures in the joints of the hands and feet. Classification systems currently describe ten closely related DA subtypes, the most severe of which is Freeman-Sheldon syndrome ( called distal arthrogryposis, type 2A [DA2A]). Children born with DA2A present with characteristic contractures of the hands, clubfeet, and facial contractures. They often develop scoliosis (Toydemir et al, 2006; Beck et al, 2013). Complications of DA, DA2A, include difficulty eating, respiratory complications, and impaired speech and mobility. Supportive treatments including bracing, physical therapy, and surgical intervention are the only therapeutic options for DA patients; these therapies are often suboptimal (Stevenson et al, 2006; Boehm et al, 2008)
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