期刊
MOLECULAR BIOLOGY OF THE CELL
卷 22, 期 15, 页码 2716-2728出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E11-01-0064
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资金
- Muscular Dystrophy Association (MDA)
- Israel Science Foundation (ISF)
- USA-Israel Binational Science Foundation (BSF)
- European Union [018690]
- German-Israel Foundation (GIF)
- Fritz-Thyssen Foundation
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 Delta K46 Caenorhabditis elegans lamin mutant, corresponding to EDMD-linked Delta K32 in human lamins A and C. Cryo-electron tomography of lamin Delta K46 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):Delta K46 lamin expressed in C. elegans was found in nuclear aggregates in postembryonic stages along with LEM-2. GFP:Delta K46 also caused mislocalization of emerin away from the nuclear periphery, consistent with a decreased ability of purified emerin to associate with lamin Delta K46 filaments in vitro. GFP:Delta K46 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 Delta K32 lamin mutation may cause EDMD in humans.
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