Lamin A Mutation and Hutchinson-Gilford Progeria

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DESCRIPTION (provided by applicant): Hutchinson-Gilford progeria syndrome (HGPS), a condition with features of premature aging, is caused by a dominant de novo mutation in LMNA, the gene that encodes lamins A and C, intermediate filament proteins associated with the nuclear envelope. The mutation in HGPS introduces an abnormal splice site that leads the expression of a lamin A mutant with 50 amino acids deleted near its carboxyl-terminal end. The mutant lamin A has been called progerin. Different mutations in lamins A and C cause cardiomyopathy and muscular dystrophy, partial lipodystrophy syndromes, a peripheral neuropathy and atypical Werner syndrome. Some of these disorders share clinical features with HGPS while others are quite different. It is not known how mutations in lamins A and C cause HGPS or other diseases. We hypothesize that different mutations in these proteins cause alterations in nuclear structure and chromatin organization that lead to abnormalities in gene expression. In HGPS, progerin expression, possibly in combination with decreased expression of normal lamins A and C, is responsible for this chain of events. Our goal is to test this hypothesis. In Aim 1, we will study the biochemistry of progerin and its effects on the cell nucleus. We will determine if progerin, like normal prelamin A, is farnesylated and processed by endoproteolysis. We will investigate the effects of progerin on nuclear and chromatin structure and on the dynamics of other nuclear envelope proteins using fluorescent photobleaching methods. In Aim 2, we will generate transgenic mice expressing progerin in epidermis and determine if they develop pathological and functional abnormalities similar to those in skin of human subjects HGPS and normal aging skin. We will also cross progerin transgenic mice to heterozygous Lmna "knockout" mice to determine if reduced wild type protein levels have additional effects. In Aim 3, we will determine if a farnesyltransferase inhibitor blocks prenylation of progerin and determine if blocking progerin prenylation reverses cellular alterations and tissue abnormalities in progerin-expressing transgenic mice, hence connecting the experimental work in Aims 1 and 2. This project will establish how mutations in nuclear lamins A and C cause HGPS, and if inhibition of protein farnesylation is a potential therapeutic intervention.