Lamins are nuclear proteins that are components of a fibrous network underlying the inner nuclear membrane termed the nuclear lamina, and are also distributed throughout the interior of the nucleus (reviewed by Goldman et al., 2002). Lamins have been classified into two types based on biochemical properties and expression patterns. B-type lamins are expressed in most cells and are encoded by two separate genes, B1 and B2, whereas the A-type lamins have been detected primarily in differentiated cell types. The lamin A gene (LMNA) encodes lamin A and C transcripts, as well as germcell-specific lamin C2. Lamins belong to the intermediate filament family of proteins and have a short N-terminal head domain followed by an ␣-helical rod domain and a globular tail domain. The C-termini of lamins A, B1 and B2 bear a CAAX motif that is post-translationally modified and, in the case of lamin A, is subjected to a further maturation step by which prelamin A is proteolytically cleaved to give mature lamin A (reviewed by Stuurman et al., 1998).Mutations in human LMNA cause several debilitating diseases, collectively termed laminopathies, that affect skeletal and cardiac muscle, adipose, bone and neuronal tissues, and also cause premature ageing syndromes. The majority of mutations cause autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) (Bonne et al., 1999), whereas other mutations cause dilated cardiomyopathy with conduction system disease (DCM) (Fatkin et al., 1999), limb girdle muscular dystrophy , or familial partial lipodystrophy (FPLD) (Shackleton et al., 2000;Cao and Hegele, 2000). Mutations in LMNA have also been linked to the relatively rare autosomal recessive disorders CharcotMarie-Tooth disorder type 2 (De Sandre-Giovannoli et al., 2002) and mandibuloacral dysplasia (Novelli et al., 2002), and more recently to restrictive dermopathy (Navarro et al., 2004). Many of the above mutations are missense mutations that occur throughout the gene, although the FPLD mutations are clustered near the C-terminus. An interesting finding has been the linkage of mutations in LMNA to Hutchinson-Gilford progeria syndrome (HGPS) (Eriksson et al., 2003; De SandreGiovannoli et al., 2003) and to atypical Werner's syndrome . The most frequent mutation in HGPS is a nucleotide substitution (GGC to GGT) that does not cause an amino acid change (G608G) but activates a cryptic splice site that leads to a deletion of 50 amino acids near the C-terminus (residues 607-656), giving rise to a truncated protein termed lamin A del50 or progerin, which retains the C-terminus of prelamin A and is not proteolytically processed. A few missense mutations such as R471C and R527C that do not affect processing of the C-terminus of lamin A have also been linked to HGPS and atypical progerias (Eriksson et al., 2003;Cao and Hegele, 2003). Cells from patients expressing mutant lamins often exhibit a range of dominant-negative effects such as abnormal nuclear morphology, aberrant lamin assembly and altered gene regulation (reviewed by Wilson, 2000;Worman...

Lamins are the major structural proteins of the nucleus in an animal cell. In addition to being essential for nuclear integrity and assembly, lamins are involved in the organization of nuclear processes such as DNA replication, transcription and repair. Mutations in the human lamin A gene lead to highly debilitating genetic disorders that primarily affect muscle, adipose, bone or neuronal tissues and also cause premature ageing syndromes. Mutant lamins alter nuclear integrity and hinder signalling pathways involved in muscle differentiation and adipocyte differentiation, suggesting tissue-specific roles for lamins. Furthermore, cells expressing mutant lamins are impaired in their response to DNA damaging agents. Recent reports indicate that certain lamin mutations act in a dominant negative manner to cause nuclear defects and cellular toxicity, and suggest a possible role for aberrant lamins in normal ageing processes.

No abstract

No abstract