Specific contribution of lamin A and lamin C in the development of laminopathies.
Mutations in the lamin A/C gene are involved in multiple human disorders for which the pathophysiological mechanisms are partially understood. Conflicting results prevail regarding the organization of lamin A and C mutants within the nuclear envelope (NE) and on the interactions of each lamin to its counterpart. We over-expressed various lamin A and C mutants both independently and together in COS7 cells. When expressed alone, lamin A with cardiac/muscular disorder mutations forms abnormal aggregates inside the NE and not inside the nucleoplasm. Conversely, the equivalent lamin C organizes as intranucleoplasmic aggregates that never connect to the NE as opposed to wild type lamin C. Interestingly, the lamin C molecules present within these aggregates exhibit an abnormal increased mobility. When co-expressed, the complex formed by lamin A/C aggregates in the NE. Lamin A and C mutants for lipodystrophy behave similarly to the wild type. These findings reveal that lamins A and C may be differentially affected depending on the mutation. This results in multiple possible physiological consequences which likely contribute in the phenotypic variability of laminopathies. The inability of lamin C mutants to join the nuclear rim in the absence of lamin A is a potential pathophysiological mechanism for laminopathies.
Sylvius
Nicolas
N
Laboratory of Genetics of Cardiac Diseases, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Canada. sylvius@cng.fr
Hathaway
Andrea
A
Boudreau
Emilie
E
Gupta
Pallavi
P
Labib
Sarah
S
Bolongo
Pierrette M
PM
Rippstein
Peter
P
McBride
Heidi
H
Bilinska
Zofia T
ZT
Tesson
Frédérique
F
D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D011232:Chemical Precipitation; D002522:Chlorocebus aethiops; D018450:Disease Progression; D030342:Genetic Diseases, Inborn / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D021381:Protein Transport; D014162:Transfection
D034904:Lamin Type A; C440308:lamin C