Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson–Gilford progeria syndrome

doi:10.1073/pnas.0600012103

Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson–Gilford progeria syndrome

*Genome Technology Branch and
^∥Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bethesda, MD 20892;
^†Department of Medical Nutrition, Karolinska Institutet, Novum, Halsovagen 7, Hiss E, Plan 6, 141 57 Huddinge, Sweden;
^‡Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101-2795;
^§Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195;
^¶CVPath, Inc., 19 Firstfield Road, Gaithersburg, MD 20878;
**Department of Pediatrics, Brown Medical School, Providence, RI 02912; and
^††National Heart, Lung, and Blood Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD 20892

Contributed by Francis S. Collins, January 2, 2006

Abstract

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.

Footnotes

^‡‡To whom correspondence should be addressed at:
National Human Genome Research Institute, National Institutes of Health, Building 31, Room 4B09, 31 Center Drive, MSC2152, Bethesda, MD 20892-2152.
E-mail: fc23a{at}nih.gov
Author contributions: R. Varga, M.E., M.R.E., M.O., I.H., F.K., E.G.N., R. Virmani, T.N.W., and F.S.C. designed research; R. Varga, M.E., M.R.E., M.O., I.H., F.K., B.C.C., J.C., D.F., S.P., H.A., H.S., X.Q., and R. Virmani performed research; R. Varga, M.E., M.R.E., M.O., I.H., F.K., B.C.C., H.S., S.G., L.B.G., R. Virmani, T.N.W., E.G.N., and F.S.C. analyzed data; and R. Varga, M.E., M.R.E., M.O., I.H., B.C.C., S.G., L.B.G., T.N.W., E.G.N., and F.S.C. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

HGPS,

Hutchinson–Gilford progeria syndrome;

VSMC,

vascular smooth muscle cells;

WT,

wild type;

BAC,

bacterial artificial chromosome;

PG,

proteoglycan;

NP,

sodium nitroprusside