Lamins in disease

The nuclear envelope (NE) creates a compartment within the interphase cell in which DNA replication, transcription and RNA processing can be regulated independently of translation. Components of the NE include the inner nuclear membrane (INM) and outer nuclear membrane (ONM), nuclear pore complexes (NPCs) and the nuclear lamina. The lamina is a fibrous nucleoskeletal structure associated with the INM through interactions with integral membrane proteins. The lamina also interlinks adjacent NPCs (reviewed by Vaughan et al., 2000). Nuclear lamins are the major components of the lamina. Analysis of cDNA sequences that encode nuclear lamins has confirmed that they are closely related to the cytoplasmic intermediate filament (IF) protein family (Fisher et al., 1986). As such, the lamins have been classified as type V IFs, and share a common primary sequence consisting of globular Nand C-terminal domains and a central α-helical rod domain. The rod domain can be divided into four α-helical segments, coil 1a, coil 1b, coil 2a, and coil 2b, which are separated by non-α-helical linker sequences (Fig. 1). Unlike the rod domains of cytoplasmic IFs, the rod domains of lamins contain an additional six heptad repeats in coil 1b. Lamins are classified as either A-type or B-type, depending on their primary sequence, behaviour at mitosis and tissue-specific expression patterns. B-type lamins are constitutively expressed in all embryonic and somatic tissues studied to date. In vertebrates, lamins B1 and B2 are closely related in sequence but are the products of separate genes. In amphibian and avian species, these lamins are expressed from the blastula stage of development onwards (Stick and Hausen, 1985; Lehner et al., 1987). B-type lamins, which are specialised for meiosis and early embryogenesis are expressed in at least some organisms. A sperm-specific B-type lamin (lamin LIV) has been identified in Xenopus (Benavente et al., 1985). In addition, lamin B3 is expressed in Xenopus oocytes and early embryos (Stick and Hausen, 1985). Lamins LIV and B3 are both the products of individual genes. A spermatocyte-specific lamin also termed lamin B3, which is a splicing variant of lamin B2, has also been identified in mouse (Furukawa and Hotta, 1993), but note that mouse lamin B3 and Xenopus lamin B3 are not homologous. The A-type lamins, lamin A and lamin C, are also alternatively spliced products of the same gene, as is the more recently described lamin A∆10, but are expressed exclusively in differentiated cells and tissues (Stick and Hausen, 1985; Lehner et al., 1987; Rober et al., 1989). Developmental control of A-type lamin expression has led to the suggestion that they stabilise differential gene expression (Nigg, 1989).