Drosophila models reveal nuclear shape and lamin localization patterns that differentiate clinically distinct laminopathies
Authors: Sydney Walker 1; Laura Hecker 2; Lori Wallrath 1
Affiliations: 1) University of Iowa; 2) Clarke University
Keywords: l. muscle disorders; o. nucleus
Laminopathies are a collection of diseases caused by mutations in the human LMNA gene, which include muscular dystrophy and lipodystrophy, an adipose tissue disorder. The symptoms and severity of laminopathies vary depending on the genetic background of the individual. The LMNA gene encodes lamins A/C, intermedicate filaments that form a meshwork underlying the inner nuclear membrane. Generating Drosophila models allows for analysis of specific mutations in a defined genetic background and the ability to express mutant lamins in specific tissues. Thus, we modeled two LMNA mutations that cause distinct clinical symptoms in Lamin C, the Drosophila orthologue of human LMNA. Both mutations cause a single amino acid substitution in the conserved Ig-like fold domain of lamins. Lamin A/C Arg482Trp causes lipodystrophy; lamin A/C Arg527Pro causes Emery-Dreifuss muscular dystrophy and lipodystrophy. Using the Gal4/UAS system, wild-type and mutant lamins were expressed in larval body wall muscles and cardiac tissue. When expressed in the larval body wall muscles, lamin Arg527Pro aggregated within the cytoplasm and caused reduced larval motility. By contrast, lamin Arg482Trp caused abnormally shaped nuclei and had no effect on larval motility. Surprisingly, both mutants caused death at the pupal stage. When expressed in cardiac tissue, lamin Arg527Pro caused a shortened adult lifespan. By contrast, flies with cardiac-specific expression of lamin Arg482Trp exhibited a lifespan similar to that of flies expressing wild-type lamin. Thus, the Drosophila models recapitulated aspects of the human disease, with only Arg527Pro affecting muscle function. In addition, the distinct intracellular localization patterns and differing effects on nuclear morphology provide an explanation for how mutations that affect the same lamin domain cause distinct clinical pathology.