title: A laminopathic mutation disrupting lamin filament assembly causes disease-like phenotypes in Caenorhabditis elegans.
abstract: Mutations in the human LMNA gene underlie many laminopathic diseases, including Emery-Dreifuss muscular dystrophy (EDMD); however, a mechanistic link between the effect of mutations on lamin filament assembly and disease phenotypes has not been established. We studied the ΔK46 Caenorhabditis elegans lamin mutant, corresponding to EDMD-linked ΔK32 in human lamins A and C. Cryo-electron tomography of lamin ΔK46 filaments in vitro revealed alterations in the lateral assembly of dimeric head-to-tail polymers, which causes abnormal organization of tetrameric protofilaments. Green fluorescent protein (GFP):ΔK46 lamin expressed in C. elegans was found in nuclear aggregates in postembryonic stages along with LEM-2. GFP:ΔK46 also caused mislocalization of emerin away from the nuclear periphery, consistent with a decreased ability of purified emerin to associate with lamin ΔK46 filaments in vitro. GFP:ΔK46 animals had motility defects and muscle structure abnormalities. These results show that changes in lamin filament structure can translate into disease-like phenotypes via altering the localization of nuclear lamina proteins, and suggest a model for how the ΔK32 lamin mutation may cause EDMD in humans.
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: Naama
authors.initials: N
authors.lastname: Wiesel-Motiuk
authors.forename: Rachel
authors.initials: R
authors.lastname: Barkan
authors.forename: Naomi
authors.initials: N
authors.lastname: Feinstein
authors.forename: Oren
authors.initials: O
authors.lastname: Lotan
authors.forename: Ohad
authors.initials: O
authors.lastname: Medalia
authors.forename: Yosef
authors.initials: Y
authors.lastname: Gruenbaum
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D020285:Cryoelectron Microscopy; D003599:Cytoskeleton / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004926:Escherichia coli; D056726:Genetic Association Studies; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009068:Movement; D009132:Muscles / Q000503:physiopathology; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D034881:Nuclear Lamina / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D010957:Plasmids; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D014169:Transformation, Bacterial
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; C092710:emerin; D049452:Green Fluorescent Proteins