Abstract
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT) within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.
Highlights
Hutchinson–Gilford progeria syndrome (HGPS) is a rare, sporadic genetic disorder with phenotypic features of premature aging [1][2,3,4]
We first focused on the different gene expression profiles in fibroblasts from controls and subjects with HGPS that were not treated with FTI
Blocking farnesylation of progerin, the truncated prelamin A expressed as a result of the G608G LMNA mutation which is responsible for most cases of HGPS, renders it less toxic
Summary
Hutchinson–Gilford progeria syndrome (HGPS) is a rare, sporadic genetic disorder with phenotypic features of premature aging [1][2,3,4] It is caused by de novo dominant mutations in LMNA [5,6,7]. Progerin toxicity is attributed at least in part to its farnesyl moiety, as chemical inhibitors of protein farnesyltransferase (FTIs) reverse abnormalities in nuclear morphology in progerin expressing cells [16,17,18,19,20]. FTIs and other chemical inhibitors of protein prenylation partially reverse progeria-like phenotypes in genetically modified mice that express progerin or lack ZMPSTE24, and accumulate unprocessed, farnesylated prelamin A [21,22,23,24]
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