Laminopathies and the long strange trip from basic cell biology to therapy
Howard J. Worman, … , Antoine Muchir, Stephen G. Young
Howard J. Worman, … , Antoine Muchir, Stephen G. Young
Published July 1, 2009
Citation Information: J Clin Invest. 2009;119(7):1825-1836. https://doi.org/10.1172/JCI37679.
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Review Series

Laminopathies and the long strange trip from basic cell biology to therapy

Abstract

The main function of the nuclear lamina, an intermediate filament meshwork lying primarily beneath the inner nuclear membrane, is to provide structural scaffolding for the cell nucleus. However, the lamina also serves other functions, such as having a role in chromatin organization, connecting the nucleus to the cytoplasm, gene transcription, and mitosis. In somatic cells, the main protein constituents of the nuclear lamina are lamins A, C, B1, and B2. Interest in the nuclear lamins increased dramatically in recent years with the realization that mutations in LMNA, the gene encoding lamins A and C, cause a panoply of human diseases (“laminopathies”), including muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. Here, we review the laminopathies and the long strange trip from basic cell biology to therapeutic approaches for these diseases.

Authors

Howard J. Worman, Loren G. Fong, Antoine Muchir, Stephen G. Young

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Figure 2

Schematic diagram outlining the posttranslational processing of nuclear lamins.

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Schematic diagram outlining the posttranslational processing of nuclear ...
Prelamin A and B-type lamins undergo 3 sequential posttranslational processing steps. First, the cysteine of the carboxyl-terminal CaaX motif is farnesylated by protein FTase. Second, the –aaX is clipped off. For prelamin A, this is likely a redundant activity of RCE1 and ZMPSTE24. Third, the newly exposed carboxyl-terminal farnesylcysteine is methylated by isoprenylcysteine carboxyl methyltransferase (ICMT). Prelamin A undergoes another step in which the carboxyl-terminal 15 amino acids, including the farnesylcysteine methyl ester, are clipped off by ZMPSTE24 and degraded, generating mature lamin A. In the setting of ZMPSTE24 deficiency, the final endoproteolytic cleavage does not occur, leading to the accumulation of a farnesylated and methylated prelamin A. ZMPSTE24 deficiency causes a severe progeroid disorder, RD. In HGPS, an alternative splicing event results in a 50–amino acid deletion in prelamin A, removing the site for the final endoproteolytic cleavage step. Thus, mature lamin A cannot be produced, and cells accumulate a mutant prelamin A that terminates with a farnesylcysteine α-methyl ester.