title: Structural and physiological phenotypes of disease-linked lamin mutations in C. elegans.
abstract: The nuclear lamina is a major structural element of the nucleus and is predominately composed of the intermediate filament lamin proteins. Missense mutations in the human lamins A/C cause a family of laminopathic diseases, with no known mechanistic link between the position of the mutation and the resulting disease phenotypes. The Caenorhabditis elegans lamin (Ce-lamin) is structurally and functionally homologous to human lamins, and recent advances have allowed detailed structural analysis of Ce-lamin filaments both in vitro and in vivo. Here, we studied the effect of laminopathic mutations on Ce-lamin filament assembly in vitro and the corresponding physiological phenotypes in animals. We focused on three disease-linked mutations, Q159K, T164P, and L535P, which have previously been shown to affect lamin structure and nuclear localization. Mutations prevented the proper assembly of Ce-lamin into filament and/or paracrystalline arrays. Disease-like phenotypes were observed in strains expressing low levels of these mutant lamins, including decreased fertility and motility coincident with muscle lesions. In addition, the Q159K- and T164P-expressing strains showed a reduced lifespan. Thus, different disease-linked mutations in Ce-lamin exhibit major effects in vivo and in vitro. Using C. elegans as a model system, a comprehensive analysis of the effects of specific lamin mutations from the level of in vitro filament assembly to the physiology of the organism will help uncover the mechanistic differences between these different lamin mutations.
authors.affiliation: Department of Genetics, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Bank
authors.forename: Kfir
authors.initials: K
authors.lastname: Ben-Harush
authors.forename: Naomi
authors.initials: N
authors.lastname: Feinstein
authors.forename: Ohad
authors.initials: O
authors.lastname: Medalia
authors.forename: Yosef
authors.initials: Y
authors.lastname: Gruenbaum
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D055032:Electron Microscope Tomography; D005298:Fertility / Q000235:genetics; D005786:Gene Expression Regulation; D007381:Intermediate Filament Proteins / Q000032:analysis / Q000737:chemistry* / Q000235:genetics; D007382:Intermediate Filaments / Q000235:genetics / Q000378:metabolism; D034882:Lamins / Q000737:chemistry* / Q000235:genetics; D020125:Mutation, Missense; D034881:Nuclear Lamina / Q000737:chemistry; D010641:Phenotype
chemical_list: D029742:Caenorhabditis elegans Proteins; D007381:Intermediate Filament Proteins; D034882:Lamins