The nuclear lamina is a proteinaceous structure located underneath the inner nuclear membrane (INM), where it associates with the peripheral chromatin. It contains lamins and lamin-associated proteins, including many integral proteins of the INM, chromatin modifying proteins, transcriptional repressors and structural proteins. A fraction of lamins is also present in the nucleoplasm, where it forms stable complexes and is associated with specific nucleoplasmic proteins. The lamins and their associated proteins are required for most nuclear activities, mitosis and for linking the nucleoplasm to all major cytoskeletal networks in the cytoplasm. Mutations in nuclear lamins and their associated proteins cause about 20 different diseases that are collectively called laminopathies’. This review concentrates mainly on lamins, their structure and their roles in DNA replication, chromatin organization, adult stem cell differentiation, aging, tumorogenesis and the lamin mutations leading to laminopathic diseases.

SummaryLamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA replication, transcription, DNA repair, and cell-cycle progression. Mutations in human LMNA gene cause several diseases termed laminopathies. One of the laminopathic diseases is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a spontaneous mutation and characterized by premature aging. HGPS phenotypes share certain similarities with several apparently comparable medical conditions, such as aging and atherosclerosis, with the conspicuous absence of neuronal degeneration and cancer rarity during the short lifespan of the patients. Cell lines from HGPS patients are characterized by multiple nuclear defects, which include abnormal morphology, altered histone modification patterns, and increased DNA damage. These cell lines provide insight into the molecular pathways including senescence that require lamins A and B1. Here, we review recent data on HGPS phenotypes through the lens of transcriptional deregulation caused by lack of functional lamin A, progerin accumulation, and lamin B1 silencing.

The nuclear lamina is a proteinaceous structure located underneath the inner nuclear membrane (INM) J. Cell. Mol. Med. Vol 13, No 6, 2009 pp. 1059-1085 © Jerusalem, Jerusalem 91904, Israel. Tel.: 972-2-6585995 Fax: 972-2-5637848 E-mail: gru@vms.huji.ac.il The lamin molecule (Fig. 1A)

Mutations in human LMNA cause Emery-Dreifuss muscular dystrophy; however, a mechanistic link between the effect of mutations on lamin filament assembly and disease phenotype has not been established. Here we show that changes in lamin filament structure translate into disease phenotypes in Caenorhabditis elegans by altering the character of the nuclear lamina.

ETOC: Caenorhabditis elegans lacking both Ce-emerin and LEM-2 show that these proteins are essential for development of specific lineages, mitosis in somatic cells, and smooth muscle activity. Reduced life span and smooth muscle activity of LEM-2–null worms predicts human LEM2 gene links to diseases more severe than Emery-Dreifuss muscular dystrophy.