Diseases of the nuclear envelope

Abstract

In the past decade, a wide range of fascinating monogenic diseases have been linked to mutations in the LMNA gene, which encodes the A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. These diseases include dilated cardiomyopathy with variable muscular dystrophy, Dunnigan-type familial partial lipodystrophy, a Charcot-Marie-Tooth type 2 disease, mandibuloacral dysplasia, and Hutchinson-Gilford progeria syndrome. Several diseases are also caused by mutations in genes encoding B-type lamins and proteins that associate with the nuclear lamina. Studies of these so-called laminopathies or nuclear envelopathies, some of which phenocopy common human disorders, are providing clues about functions of the nuclear envelope and insights into disease pathogenesis and human aging.

Figure 1.

Schematic diagram of a prelamin A molecule with mutations causing laminopathies indicated. Mutations causing Dunnigan-type famililal partial lipodystrophy (FPLD, dark blue asterisks), Charcot-Marie-Tooth disease (CMT, orange asterisk), mandibuloacral dysplasia (MAD, light blue asterisks), or Hutchinson-Gilford progeria syndrome (HGPS, purple asterisk) are found in specific areas of the molecule, whereas mutations causing myopathies (red asterisks) are found throughout. Mutation data are from Leiden Muscular Dystrophy pages (http://www.dmd.nl/lmna_home.html). Photographs are reproduced with permission from Elsevier (Chaouch et al. 2003; Emery 2000; Novelli et al. 2002), Macmillan Publishers Ltd (Peters et al. 1998; Towbin and Bowles 2002), and the American Association for the Advancement of Science (De Sandre-Giovannoli et al. 2003).

Figure 2.

Processing of prelamin A to mature lamin A in wild-type (WT) cells occurs in several steps, described in the text (middle column). In restrictive dermopathy (RD), the ZMPSTE24 enzyme is nonfunctioning, resulting in accumulation of farnesylated prelamin A (left column). In Hutchinson-Gilford progeria syndrome (HGPS), the second cleavage site for ZMPSTE24 is deleted, resulting in accumulation of a truncated form of farnesylated prelamin A (right column).