Description
Distal arthrogryposis (DA) is a group of autosomal dominant diseases in skeletal muscle. It is characterized by multiple congenital contractures of distal joints of the limbs absent of primary neurological defect. Based on differing severities of muscle contractures, DA can be classified into different types. Freeman-Sheldon Syndrome (FSS) is the most severe DA syndrome categorized as DA2A. Sheldon-Hall Syndrome (SHS) is the most common syndrome categorized as DA2B. The weakest type of DA is called DA1. Recent studies have shown that the most common causes of DA are mutations in the embryonic myosin heavy chain gene (MYH3). Although several such mutations have been identified in patients, the mechanisms of these syndromes are still unknown due to lack of disease models. In this study, I have created transgenic Drosophila melanogaster (fruit fly) models with MYH3 mutations to recapitulate human DA phenotypes. These mutations included A234T (DA2B mutation) and F437I (DA1 mutation). My results showed that the homologs of human DA mutations caused significant defects in Drosophila flight ability, jump ability, viability and muscle ultrastructure of transgenic flies. DA2B flies showed higher severity of phenotype compared to DA1 flies, and homozygotes had more severe phenotypes versus heterozygotes. Overall, this study used these new Drosophila models of human distal arthrogryposis to identify functional and structural defects caused by DA mutations, and indicated that these specific mutations disrupt myosin function.
