TY - JOUR
T1 - Structural and physiological phenotypes of disease-linked lamin mutations in C. elegans
AU - Bank, Erin M.
AU - Ben-Harush, Kfir
AU - Feinstein, Naomi
AU - Medalia, Ohad
AU - Gruenbaum, Yosef
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
KW - Caenorhabditis elegans
KW - EDMD
KW - HGPS
KW - Laminopathic diseases
KW - Nuclear lamina
UR - http://www.scopus.com/inward/record.url?scp=84855843405&partnerID=8YFLogxK
U2 - 10.1016/j.jsb.2011.10.009
DO - 10.1016/j.jsb.2011.10.009
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C2 - 22079399
AN - SCOPUS:84855843405
SN - 1047-8477
VL - 177
SP - 106
EP - 112
JO - Journal of Structural Biology
JF - Journal of Structural Biology
IS - 1
ER -