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We investigated whether or not human disease-causing, amino acid substitutions in  MYH9  could cause dominant phenotypes when introduced into the sole non-muscle myosin II heavy chain in  Drosophila melanogaster  ( zip /MyoII). We characterized  in vivo  the effects of four  MYH9 -like mutations in the myosin rod—R1171C, D1430N, D1847K and R1939X—which occur at highly conserved residues. These engineered mutant heavy chains resulted in  D .  melanogaster  non-muscle myosin II with partial wild-type function. In a wild-type genetic background, mutant heavy chains were overtly recessive and hypomorphic: each was able to substitute partially for endogenous non-muscle myosin II heavy chain in animals lacking zygotically produced heavy chain (but the penetrance of rescue was below Mendelian expectation). Moreover, each of the four mutant heavy chains exhibits dominant characteristics when expressed in a sensitized genetic background (flies heterozygous for  RhoA  mutations). Thus, these  zip /MyoII  MYH9   alleles function, like certain other hypomorphic alleles, as excellent bait in screens for genetic interactors. Our conjecture is that these mutations in  D .  melanogaster  behave comparably to their parent mutations in humans. We further characterized these  zip /MyoII  MYH9   alleles, and found that all were capable of correct spatial and temporal localization in animals lacking zygotic expression of wild-type  zip /MyoII.  In vitro , we demonstrate that mutant heavy chains can dimerize with endogenous, wild-type heavy chains, fold into coiled-coil structures and assemble into higher-order structures. Our work further supports  D. melanogaster  as a model system for investigating the basis of human disease.

human molecular genetics

An  MYH9  human disease model in flies: site-directed mutagenesis of the  Drosophila  non-muscle myosin II results in hypomorphic alleles with dominant character