Prelamin A farnesylation and progeroid syndromes.
Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation that leads to the synthesis of a mutant prelamin A that is farnesylated but cannot be further processed to mature lamin A. A more severe progeroid disorder, restrictive dermopathy (RD), is caused by the loss of the prelamin A-processing enzyme, ZMPSTE24. The absence of ZMPSTE24 prevents the endoproteolytic processing of farnesyl-prelamin A to mature lamin A and leads to the accumulation of farnesyl-prelamin A. In both HGPS and RD, the farnesyl-prelamin A is targeted to the nuclear envelope, where it interferes with the integrity of the nuclear envelope and causes misshapen cell nuclei. Recent studies have shown that the frequency of misshapen nuclei can be reduced by treating cells with a farnesyltransferase inhibitor (FTI). Also, administering an FTI to mouse models of HGPS and RD ameliorates the phenotypes of progeria. These studies have prompted interest in testing the efficacy of FTIs in children with HGPS.
Young
Stephen G
SG
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. sgyoung@mednet.ucla.edu
Meta
Margarita
M
Yang
Shao H
SH
Fong
Loren G
LG
D000818:Animals; D006801:Humans; D034904:Lamin Type A; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011371:Progeria / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017368:Protein Prenylation / Q000235:genetics; D013577:Syndrome
D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A