A laminopathic mutation disrupting lamin filament assembly causes disease-like phenotypes in Caenorhabditis elegans

作者：Bank Erin M; Ben Harush Kfir; Wiesel Motiuk Naama; Barkan Rachel; Feinstein Naomi; Lotan Oren; Medalia Ohad; Gruenbaum Yosef^*

来源：Molecular Biology of the Cell, 2011, 22(15): 2716-2728.

DOI：10.1091/mbc.E11-01-0064

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.

• 出版日期2011-8-1