A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization.
Numerous mutations in the human A-type lamin gene (LMNA) cause the premature aging disease, progeria. Some of these are located in the alpha-helical central rod domain required for the polymerization of the nuclear lamins into higher order structures. Patient cells with a mutation in this domain, 433G>A (E145K) show severely lobulated nuclei, a separation of the A- and B-type lamins, alterations in pericentric heterochromatin, abnormally clustered centromeres, and mislocalized telomeres. The induction of lobulations and the clustering of centromeres originate during postmitotic nuclear assembly in daughter cells and this early G1 configuration of chromosomes is retained throughout interphase. In vitro analyses of E145K-lamin A show severe defects in the assembly of protofilaments into higher order lamin structures. The results show that this central rod domain mutation affects nuclear architecture in a fashion distinctly different from the changes found in the most common form of progeria caused by the expression of LADelta50/progerin. The study also emphasizes the importance of lamins in nuclear assembly and chromatin organization.
Taimen
Pekka
P
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Pfleghaar
Katrin
K
Shimi
Takeshi
T
Möller
Dorothee
D
Ben-Harush
Kfir
K
Erdos
Michael R
MR
Adam
Stephen A
SA
Herrmann
Harald
H
Medalia
Ohad
O
Collins
Francis S
FS
Goldman
Anne E
AE
Goldman
Robert D
RD
D019943:Amino Acid Substitution / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D002503:Centromere / Q000378:metabolism; D045584:Chromosome Positioning; D002877:Chromosomes, Human / Q000378:metabolism* / Q000648:ultrastructure; D003460:Crystallization; D004261:DNA Replication; D006367:HeLa Cells; D006570:Heterochromatin / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000648:ultrastructure; D008297:Male; D008938:Mitosis; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011371:Progeria / Q000235:genetics*; D016615:Telomere / Q000378:metabolism
D006570:Heterochromatin; C494847:LMNA protein, human; D034904:Lamin Type A; D050505:Mutant Proteins