Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, commonly caused by a point mutation in the lamin A gene that results in a protein lacking 50 aa near the C terminus, denoted LADelta50. Here we show by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsen as HGPS cells age in culture, and their severity correlates with an apparent increase in LADelta50. Introduction of LADelta50 into normal cells by transfection or protein injection induces the same changes. We hypothesize that these alterations in nuclear structure are due to a concentration-dependent dominant-negative effect of LADelta50, leading to the disruption of lamin-related functions ranging from the maintenance of nuclear shape to regulation of gene expression and DNA replication.
Goldman
Robert D
RD
Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA. r-goldman@northwestern.edu
Shumaker
Dale K
DK
Erdos
Michael R
MR
Eriksson
Maria
M
Goldman
Anne E
AE
Gordon
Leslie B
LB
Gruenbaum
Yosef
Y
Khuon
Satya
S
Mendez
Melissa
M
Varga
Renée
R
Collins
Francis S
FS
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D022003:Cell Nucleus Structures / Q000648:ultrastructure*; D016922:Cellular Senescence / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007223:Infant; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics; D009685:Nuclear Envelope / Q000648:ultrastructure; D011371:Progeria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017384:Sequence Deletion
D034904:Lamin Type A