Nuclear lamin functions and disease

Abstract

Recent studies have shown that premature cellular senescence and normal organ development and function depend on the type V intermediate filament proteins, the lamins, which are major structural proteins of the nucleus. This review presents an up-to-date summary of the literature describing new findings on lamin functions in various cellular processes and emphasizes the relationship between the lamins and devastating diseases ranging from premature aging to cancer. Recent insights into the structure and function of the A- and B- type lamins in normal cells and their dysfunctions in diseased cells are providing novel targets for the development of new diagnostic procedures and disease intervention. We summarize these recent findings, focusing on data from mice and humans, and highlight the expanding knowledge of these proteins in both healthy and diseased cells.

Figure 1

A partial summary of mutations in lamin A/C. The mutations are categorized into those involving primarily adipose tissue (lipodystrophy) (orange), cardiac muscle (cardiomyopathy) (blue), skeletal muscle (muscular dystrophy and myopathy) (green), and premature aging (atypical Werner’s, HGPS, atypical progeria) (red). Due to the large number of mutations identified in LMNA, only those mutations resulting in amino acid substitutions resulting in the production of a full length lamin A/C are included, with the exception of the 50 amino acid deletion in HGPS. Other mutations involving deletions, premature stop codons, and insertions are not included. The information on mutations and their associated diseases was obtained from the Leiden Muscular Dystrophy pages (www.dmd.nl/lmna) and the Human Intermediate Filament Database (www.interfil.org) [98].

Figure 2

Changes in the nuclear envelope/lamina of HGPS, APS, and cancer cells. (A) Double labeling with lamin A/C (red) and lamin B (green) of an HGPS cell [37]. (B) Flower-shaped nucleus of an APS cell with the E145K mutation stained for lamin A (red) and centromeres (CREST antiserum, green) showing that centromeres are clustered in the central region of the nucleus instead of their normally dispersed nuclear distribution [46]. (C) Metastatic breast cancer cell MDA MB435 labeled for lamin A/C (red) and lamin B (green).