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.
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Renee
R
Varga
Maria
M
Eriksson
Michael R
MR
Erdos
Michelle
M
Olive
Ingrid
I
Harten
Frank
F
Kolodgie
Brian C
BC
Capell
Jun
J
Cheng
Dina
D
Faddah
Stacie
S
Perkins
Hedwig
H
Avallone
Hong
H
San
Xuan
X
Qu
Santhi
S
Ganesh
Leslie B
LB
Gordon
Renu
R
Virmani
Thomas N
TN
Wight
Elizabeth G
EG
Nabel
Francis S
FS
Collins
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