Mutations in LMNA, the gene for lamin A/C, have been shown to cause several forms of muscular dystrophy, a cardiomyopathy, familial partial lipodystrophy, one form of Charcot Marie Tooth neuropathy, mandibuloacral dysplasia, and Hutchinson Gilford progeria syndrome (HGPS). HGPS patients have many aging-like phenotypes, including a wizened appearance, alopecia, osteoporosis, and coronary heart disease. HGPS is a merciless disease;death occurs on average at age 13, nearly always from atherosclerosis in the coronary and cerebral arteries. A recent NIH workshop on HGPS concluded that a thorough understanding of vascular disease in HGPS syndrome represents a key research priority. In most cases, HGPS is caused by a de novo single nucleotide substitution in exon 11. This mutation generates a cryptic splice site, resulting in an in-frame deletion of 50 amino acids near the carboxyl terminus of the lamin A. Interestingly, the deletion prevents the endoproteolytic processing of prelamin A. The objective of this grant application is to create mouse models of HGPS for the purpose of exploring mechanisms underlying the strikingly increased susceptibility to atherosclerosis in HGPS. The Principal Investigator (PI), Dr. Stephen G. Young, is well-positioned to pursue this objective. For the past 10 years, the PI has worked both on the posttranslational processing enzymes required for the biogenesis of lamin A and on the genetic underpinnings of atherosclerosis. For both projects, the PI has relied heavily on studies with gene targeted mice. Recently, the PI showed that the targeted inactivation of Zmpste24 prevents the proper endoproteolytic processing of lamin A, leading to the accumulation of prelamin A. Of note, Zmpste24-/- mice have a host of phenotypes similar to those in HGPS. The PI has also created mice lacking other enzymes involved in the posttranslational processing of the lamins (protein farnesyltransferase, Rcel, and Icmt).
The first aim of this application is to create, with gene-targeting approaches, authentic mouse models of HGPS. The second specific aim is to compare, at both cellular and whole-animal levels, phenotypes in HGPS mouse models and the Zmpste24-deficient mice. The third specific aim is to understand mechanisms underlying the strikingly high susceptibility to atherosclerosis in HGPS. The PI's laboratory has extensive experience in analyzing atherogenesis in mice and is thrilled with the prospect of exploring mechanisms of atherosclerosis in HGPS.
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