Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome.
Children with Hutchinson-Gilford progeria syndrome (HGPS) suffer from dramatic acceleration of some symptoms associated with normal aging, most notably cardiovascular disease that eventually leads to death from myocardial infarction and/or stroke usually in their second decade of life. For the vast majority of cases, a de novo point mutation in the lamin A (LMNA) gene is the cause of HGPS. This missense mutation creates a cryptic splice donor site that produces a mutant lamin A protein, termed "progerin," which carries a 50-aa deletion near its C terminus. We have created a mouse model for progeria by generating transgenics carrying a human bacterial artificial chromosome that harbors the common HGPS mutation. These mice develop progressive loss of vascular smooth muscle cells in the medial layer of large arteries, in a pattern very similar to that seen in children with HGPS. This mouse model should prove valuable for testing experimental therapies for this devastating disorder and for exploring cardiovascular disease in general.
Varga
Renee
R
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Eriksson
Maria
M
Erdos
Michael R
MR
Olive
Michelle
M
Harten
Ingrid
I
Kolodgie
Frank
F
Capell
Brian C
BC
Cheng
Jun
J
Faddah
Dina
D
Perkins
Stacie
S
Avallone
Hedwig
H
San
Hong
H
Qu
Xuan
X
Ganesh
Santhi
S
Gordon
Leslie B
LB
Virmani
Renu
R
Wight
Thomas N
TN
Nabel
Elizabeth G
EG
Collins
Francis S
FS
D000818:Animals; D001794:Blood Pressure; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009131:Muscle, Smooth, Vascular / Q000002:abnormalities* / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D011371:Progeria / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D019076:Transgenes / Q000235:genetics
D034904:Lamin Type A