Progeria: a paradigm for translational medicine

Abstract

Rare diseases are powerful windows into biological processes and can serve as models for the development of therapeutic strategies. The progress made on the premature aging disorder Progeria is a shining example of the impact that studies of rare diseases can have.

Figure 1.. HGPS: From Genetics to Symptoms

HGPS is caused by a spontaneous point mutation in the LMNA gene, coding for the nuclear intermediate filament proteins lamin A and C. The disease mutation activates an alternative pre-mRNA splice site in exon 11 that results in removal of 150 nt from the 3′ end of this exon and creates an internal deletion of 50 aa in the translated lamin A protein. The mutant protein (red), referred to as progerin, is permanently farnesylated as the 50 aa deletion includes an endoproteolytic cleavage site, which normally removes the farnesylated C terminus from the wild-type protein. The farnesyl group is believed to facilitate the association of the protein to the nuclear membrane, resulting in its accumulation at the nuclear periphery. Association of progerin with the lamina interferes with normal lamina function and triggers, via yet unknown mechanisms, many of the commonly observed nuclear defects. HGPS cells also exhibit nonnuclear defects, including altered signaling and metabolic properties. It is assumed that these cellular defects and particularly the loss of stem cell function contribute to the prominent overt patient symptoms. (Left) Fluorescently tagged progerin (green) accumulates at the periphery of patient nuclei and alters nuclear morphology. (Right) Two progeria patients. Image reproduced with permission, courtesy of The Progeria Research Foundation.

Figure 2.. A Spectrum of Possible HGPS Therapies

HGPS is amenable to a wide spectrum of cutting-edge therapeutic strategies.