Lamin A-linked progerias: is farnesylation the be all and end all?
HGPS (Hutchinson-Gilford progeria syndrome) is a severe childhood disorder that appears to mimic an accelerated aging process. The disease is most commonly caused by gene mutations that disrupt the normal post-translational processing of lamin A, a structural component of the nuclear envelope. Impaired processing results in aberrant retention of a farnesyl group at the C-terminus of lamin A, leading to altered membrane dynamics. It has been widely proposed that persistence of the farnesyl moiety is the major factor responsible for the disease, prompting clinical trials of farnesyltransferase inhibitors to prevent lamin A farnesylation in children afflicted with HGPS. Although there is evidence implicating farnesylation in causing some of the cellular defects of HGPS, results of several recent studies suggest that aberrant lamin A farnesylation is not the only determinant of the disease. These findings have important implications for the design of treatments for this devastating disease.
Smallwood
Dawn T
DT
Department of Biochemistry, Henry Wellcome Building, University of Leicester, Leicester LE1 9HN, UK.
Shackleton
Sue
S
D000595:Amino Acid Sequence; D002648:Child; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007223:Infant; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009685:Nuclear Envelope / Q000378:metabolism; D010641:Phenotype; D054876:Prenylation; D011371:Progeria / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
D004791:Enzyme Inhibitors; D034904:Lamin Type A; D051231:Farnesyltranstransferase