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 1

The nuclear lamina.

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The nuclear lamina. (A) The nuclear lamina is a meshwork of IFs localize...
(A) The nuclear lamina is a meshwork of IFs localized primarily to the nucleoplasmic face of the inner nuclear membrane (shown schematically in red). The lamins interact with several integral proteins of the inner nuclear membrane, including lamin B receptor (LBR), MAN1 (encoded by the LEMD3 gene), emerin, lamina-associated polypeptide 1 (LAP), LAP2β, small nesprin 1 isoforms, and SUNs. SUNs interact with large nesprin 2 isoforms, integral proteins of the outer nuclear membrane, which also interact with actin, linking the nuclear lamina to the cytoskeleton. (B) In humans, 3 genes encode nuclear lamins. LMNA on chromosome 1q21.2 encodes the A-type lamins, with prelamin A and lamin C generated by alternative RNA splicing being the major somatic cell isoforms. Prelamin A has 98 unique amino acids and lamin C 6 unique amino acids at their carboxyl terminus (gray striping). LMNB1 on chromosome 5q23.3–q31.1 encodes lamin B1, and LMNB2 on chromosome 19p13.3 encodes lamin B2, the somatic cell B-type lamins. All the lamins have conserved α-helical rod domains and variable head and tail domains preceding and following the central rod domain. The nuclear localization signals are located in the tail domain (indicated in red). Prelamin A, lamin B1, and lamin B2 have carboxyl-terminal CaaX motifs, a signal for protein farnesylation.