Processing of lamin A in normal and HGPS cells. (A) A photograph of a 3.5-yr-old HGPS patient with a classic HGPS mutation (photo courtesy of The Progeria Research Foundation). (B, left) The process of maturation of pre–lamin A. The first three steps are common to all CAAX proteins, including all B-type lamins. Inhibition of the second or third steps results in toxic lamin A accumulation, causing HGPS, restricted dermopathy (RD), or mandibuloacral dysplasia (MAD). The fourth step involves cleavage of 15 amino acids away from the terminal cysteine by Zmpste24. (right) The processing of pre–lamin A in the most common HGPS mutation, which deletes amino acids 607–656 (progerin/LAΔ50), including the second cleavage site of lamin A by Zmpste24. The scheme in B was modified from Mattout et al. (2006).