fig1

Figure 1. Post-translation modification of LMNA. (A) The LMNA gene, which is comprised of 12 exons, encodes the prelamin A/C protein, which undergoes farnesylation of the cysteine residue at the CaaX motif at the COOH terminus (amino acids CSIM), which is then cleaved by ZMPSTE24 or FACE1, leading to the removal of the SIM amino acids. This is followed by carboxylation of the cysteine residue by isoprenylcysteine carboxyl methyltransferase (ICMT). The carboxylated protein is cleaved at RSY^LLG recognition motif by the ZMPSTE24, resulting in the removal of the last 18 amino acids from the protein and producing the mature LMNA protein. (B) In the classic Hutchinson-Gilford Progeria Syndrome (HGPS), a C>T transition in exon 11 of the gene, while a synonymous variant, introduced a cryptic splicing site, which removes 150 nucleotides from the mRNA. Thus, the prelamin A/C protein has a deletion of 50 amino acids near the COOH terminal of the protein. The protein undergoes farnesylation, removal of the SIM amino acids at the COOH terminal, and carboxylation of the cysteine residue. However, because of the deletion of the 50 amino acids, the ZMPSTE24 recognition site is deleted, and consequently, the farnesylated/carboxylated mutant pre-LMNA referred to as progerin, accumulates in the nucleus.