The laminopathies: nuclear structure meets disease by Mounkes et al
Introduction: structure and function of the nuclear envelope
Nuclear envelope (NE) is interface between nucleus and rest of cell. Consist of inner and outer nuclear membranes (INM and ONM). Between them is perinuclear space (PNS). ONM is contiguous with rough ER. Both membranes have many attached ribosome.
INM is associated with chromatin. INM, ONM and ER are a single continuous membrane system extending from nucleus. PNS is an extension of ER lumen.
Under INM is nuclear lamina, a thin filamentous meshwork Lamina defines interphase nuclear architecture DNA replication and chromatin organisation. Major components are nuclear lamins, type A and B.
Nuclear lamins have central α-helical nrod domain. Flanked by small nonhelical amino terminal sequence and a larger C-terminal globular domain. Lamin monomers associated to form parallel coiled coil homodimers.
LMNA encodes 4 proteins that arise by alternate splicing. They produce 2 major A-type lamin, Lamin A and Lamin C. They diverge at the C terminin. Lamin A has a unique C terminal extension which undergoes post-translational modifications eg farneslyation and protelolytic cleavage. These are required for Lamin A to insert into INM. Lamin C cannot be farnesylated. Its incorporation into nuclear lamina depends on Lamin A.
Lamin A and C expression are developmentally regulated.
Laminopathies are inherited disease. They arise through mutations in genes coding type A lamins and lamina-associated proteins.
In EDMD, mutations in X-linked gene STA. It is a muscular dystrophy. Contractions in Achilles and elbow tendons rigid spine muscle weakness. Abrnoaml heart rhythms, heart block and cardiomyopathy leading to cardiac arrest. STA gene encodes nuclear protein Emerin. Emerin is a 29kDa integral membrane protein traversing the INM through its C terminal domain. Most of protein is in nucleoplasm where it interacts with other nuclear proteins. STA mutations result in absence of detectable emerin or its mislocalisation to ER. Loss of emerin from NE.
Pelger-Huet anomaly is caused by mutations in LBR gene. Developmental delay, epilepsy, skeletal abnormalities, changes to nuclear morphology and chromatin organisation in granulocytes. In mice LBR gene maps to icthyosis locus.
Molecular and cellular mechanisms underlying the laminopathies
Expression of mutant A type lamins may affect structural integrity of nucleus. Susceptible to physical stress. Lmna-/- nuclei show redistribution of NE-associated proteins and increased fragility. NE protein redistribution is associated with localised separation of ONM from INM. Increases intramembraneous perinuclear space at site of separation. Nuclear contents are retained by INM only in specific regions. This may cause pathology in tissues subject to mechanical stress eg skeletal and mardiac muscles. Contracticle forces rupture weaker ucleir.
LMNA mutations may affect nuclear structure of function and affect gene expression. Interaction between interphase cytoskeleton/cell surface with structural organisation and function of nucleus esp location of nucleus in cell and regulation of gene expression by mechanical signalling. Nuclear position may be important in licessencepahly, neuronal disease. Caused by changes to LIS1 which codes regulator of dynein-dynactin complex. Required for appropriate migration of nuclei.
Nesprin proteins localise to NE and interact with cytoskeleton. The genes encode giant proteins containing actin-binding calponin homology domains at N terminus an a central region with many spectrin repeats. C termini of Nesprins consist of a highly conserved KLS/KASH motif with a TM domain and short cyto/nucleoplasmic sequence. Alternate splicing causes many different forms. Antibodies to N terminal regions show mainly cytoplasmic distribution with localisation to Z lines in muscle cell sarcomeres. Antibodies to C terminal domain show localisation to NE and weaker presence in nucleoplasm. Nesprins interact with A type lamins and emerin. In worm, localisation of specific gene to NE depends on NE proteins NC-83 and UNC-84. UNC-84 positioning depends on lamin expression. Mutations in ANC-1 cause nuclei of hypodermal syncitium to float freely in cytoplasm and form clusters. Nesprins seem to be required to anchor nucleus to interphase cytoskeleton. During interphase, this interaction may be important to transmit mechanically induced signalling form cell surface to nucleus.
Disrupting nuclear lamina may affect chromatin organisation and transcriptional regulation of gene expression in specific ways. Many proteins associated with NE may be involved in chromatin organisation, transcription and binding DNA. Heterochromatin is often at nuclear periphery. Gene silencing correlates with relocation silenced gene to periphery. NE-associated proteins may regulate gene expression.
Loss of Lamin A in mice causes redistribution ofemerin from nucleus to ER. Mutations associated with skeletal/cardiac muscle laminopathies affect emerin distribution and lamin localisation at NE and NE morphology.
Splicing mutations at 3' end of lamin A gene cause deletions in C temrinal globular domain. Associated with premature ageing syndrome, Hutchinson-Gilford Progeria.