InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: LMNA

Summary

InnateDB Protein

IDBP-103384.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

LMNA

Protein Name

lamin A/C

Synonyms

CDCD1; CDDC; CMD1A; CMT2B1; EMD2; FPL; FPLD; FPLD2; HGPS; IDC; LDP1; LFP; LGMD1B; LMN1; LMNC; LMNL1; PRO1;

Species

Homo sapiens

Ensembl Protein

ENSP00000357283

InnateDB Gene

IDBG-103380 (LMNA)

Protein Structure

UniProt Annotation

Function

Lamins are components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane, which is thought to provide a framework for the nuclear envelope and may also interact with chromatin. Lamin A and C are present in equal amounts in the lamina of mammals. Plays an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics. Required for normal development of peripheral nervous system and skeletal muscle and for muscle satellite cell proliferation. Required for osteoblastogenesis and bone formation. Also prevents fat infiltration of muscle and bone marrow, helping to maintain the volume and strength of skeletal muscle and bone.Prelamin-A/C can accelerate smooth muscle cell senescence. It acts to disrupt mitosis and induce DNA damage in vascular smooth muscle cells (VSMCs), leading to mitotic failure, genomic instability, and premature senescence.

Subcellular Localization

Nucleus. Nucleus envelope. Nucleus lamina. Nucleus, nucleoplasm. Note=Farnesylation of prelamin-A/C facilitates nuclear envelope targeting and subsequent cleaveage by ZMPSTE24/FACE1 to remove the farnesyl group produces mature lamin- A/C, which can then be inserted into the nuclear lamina. EMD is required for proper localization of non-farnesylated prelamin-A/C.Isoform C: Nucleus speckle {ECO:0000269PubMed:16061563}.

Disease Associations

Emery-Dreifuss muscular dystrophy 2, autosomal dominant (EDMD2) [MIM:181350]: A form of Emery-Dreifuss muscular dystrophy, a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system, early contractures of the elbows, Achilles tendons and spine, and cardiomyopathy associated with cardiac conduction defects. {ECO:0000269PubMed:10080180, ECO:0000269PubMed:10739764, ECO:0000269PubMed:10908904, ECO:0000269PubMed:10939567, ECO:0000269PubMed:11503164, ECO:0000269PubMed:12032588, ECO:0000269PubMed:12649505, ECO:0000269PubMed:14684700, ECO:0000269PubMed:14985400, ECO:0000269PubMed:15744034, ECO:0000269PubMed:20848652}. Note=The disease is caused by mutations affecting the gene represented in this entry.Emery-Dreifuss muscular dystrophy 3, autosomal recessive (EDMD3) [MIM:181350]: A form of Emery-Dreifuss muscular dystrophy, a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system, early contractures of the elbows, Achilles tendons and spine, and cardiomyopathy associated with cardiac conduction defects. {ECO:0000269PubMed:22431096}. Note=The disease is caused by mutations affecting the gene represented in this entry.Cardiomyopathy, dilated 1A (CMD1A) [MIM:115200]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269PubMed:10580070, ECO:0000269PubMed:11561226, ECO:0000269PubMed:11897440, ECO:0000269PubMed:12486434, ECO:0000269PubMed:12628721, ECO:0000269PubMed:12920062, ECO:0000269PubMed:14684700, ECO:0000269PubMed:15140538, ECO:0000269PubMed:15219508, ECO:0000269PubMed:16061563, ECO:0000269PubMed:20160190, ECO:0000269PubMed:21846512}. Note=The disease is caused by mutations affecting the gene represented in this entry.Lipodystrophy, familial partial, 2 (FPLD2) [MIM:151660]: A disorder characterized by the loss of subcutaneous adipose tissue in the lower parts of the body (limbs, buttocks, trunk). It is accompanied by an accumulation of adipose tissue in the face and neck causing a double chin, fat neck, or cushingoid appearance. Adipose tissue may also accumulate in the axillae, back, labia majora, and intraabdominal region. Affected patients are insulin-resistant and may develop glucose intolerance and diabetes mellitus after age 20 years, hypertriglyceridemia, and low levels of high density lipoprotein cholesterol. {ECO:0000269PubMed:10587585, ECO:0000269PubMed:10655060, ECO:0000269PubMed:10739751, ECO:0000269PubMed:12015247, ECO:0000269PubMed:12196663, ECO:0000269PubMed:12629077, ECO:0000269PubMed:17250669}. Note=The disease is caused by mutations affecting the gene represented in this entry.Limb-girdle muscular dystrophy 1B (LGMD1B) [MIM:159001]: An autosomal dominant degenerative myopathy with age-related atrioventricular cardiac conduction disturbances, dilated cardiomyopathy, and the absence of early contractures. Characterized by slowly progressive skeletal muscle weakness of the hip and shoulder girdles. Muscle biopsy shows mild dystrophic changes. {ECO:0000269PubMed:10814726, ECO:0000269PubMed:11525883, ECO:0000269PubMed:12032588, ECO:0000269PubMed:12673789, ECO:0000269PubMed:15744034, ECO:0000269PubMed:17136397}. Note=The disease is caused by mutations affecting the gene represented in this entry.Charcot-Marie-Tooth disease 2B1 (CMT2B1) [MIM:605588]: A recessive axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. Nerve conduction velocities are normal or slightly reduced. {ECO:0000269PubMed:11799477}. Note=The disease is caused by mutations affecting the gene represented in this entry.Hutchinson-Gilford progeria syndrome (HGPS) [MIM:176670]: Rare genetic disorder characterized by features reminiscent of marked premature aging. {ECO:0000269PubMed:12714972, ECO:0000269PubMed:12768443, ECO:0000269PubMed:12927431, ECO:0000269PubMed:15286156, ECO:0000269PubMed:15622532, ECO:0000269PubMed:21791255}. Note=The disease is caused by mutations affecting the gene represented in this entry. HGPS is caused by the toxic accumulation of a truncated form of lamin-A/C. This mutant protein, called progerin (isoform 6), acts to deregulate mitosis and DNA damage signaling, leading to premature cell death and senescence. The mutant form is mainly generated by a silent or missense mutation at codon 608 of prelamin A that causes activation of a cryptic splice donor site, resulting in production of isoform 6 with a deletion of 50 amino acids near the C terminus. Progerin lacks the conserved ZMPSTE24/FACE1 cleavage site and therefore remains permanently farnesylated. Thus, although it can enter the nucleus and associate with the nuclear envelope, it cannot incorporate normally into the nuclear lamina (PubMed:12714972). {ECO:0000269PubMed:12714972}.Cardiomyopathy, dilated, with hypergonadotropic hypogonadism (CMDHH) [MIM:212112]: A disorder characterized by the association of genital anomalies, hypergonadotropic hypogonadism and dilated cardiomyopathy. Patients can present other variable clinical manifestations including mental retardation, skeletal anomalies, scleroderma-like skin, graying and thinning of hair, osteoporosis. Dilated cardiomyopathy is characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. {ECO:0000269PubMed:12927431, ECO:0000269PubMed:17150192, ECO:0000269PubMed:19283854}. Note=The disease is caused by mutations affecting the gene represented in this entry.Mandibuloacral dysplasia with type A lipodystrophy (MADA) [MIM:248370]: A disorder characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of the cranial suture, progeroid appearance, partial alopecia, soft tissue calcinosis, joint contractures, and partial lipodystrophy with loss of subcutaneous fat from the extremities. Adipose tissue in the face, neck and trunk is normal or increased. {ECO:0000269PubMed:12075506, ECO:0000269PubMed:15998779, ECO:0000269PubMed:16278265}. Note=The disease is caused by mutations affecting the gene represented in this entry.Lethal tight skin contracture syndrome (LTSCS) [MIM:275210]: Rare disorder mainly characterized by intrauterine growth retardation, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, facial features (small mouth, small pinched nose and micrognathia), sparse/absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia, multiple joint contractures and an early neonatal lethal course. Liveborn children usually die within the first week of life. The overall prevalence of consanguineous cases suggested an autosomal recessive inheritance. {ECO:0000269PubMed:15317753}. Note=The disease is caused by mutations affecting the gene represented in this entry.Heart-hand syndrome Slovenian type (HHS-Slovenian) [MIM:610140]: Heart-hand syndrome (HHS) is a clinically and genetically heterogeneous disorder characterized by the co- occurrence of a congenital cardiac disease and limb malformations. {ECO:0000269PubMed:18611980}. Note=The disease is caused by mutations affecting the gene represented in this entry.Muscular dystrophy congenital LMNA-related (MDCL) [MIM:613205]: A form of congenital muscular dystrophy. Patients present at birth, or within the first few months of life, with hypotonia, muscle weakness and often with joint contractures. {ECO:0000269PubMed:18551513}. Note=The disease is caused by mutations affecting the gene represented in this entry.Note=Defects in LMNA may cause a late-onset cardiocutaneous progeria syndrome characterized by cutaneous manifestations of aging appearing in the third decade of life, cardiac valve calcification and dysfunction, prominent atherosclerosis, and cardiomyopathy, leading to death on average in the fourth decade. {ECO:0000269PubMed:23666920}.

Tissue Specificity

In the arteries, prelamin-A/C accumulation is not observed in young healthy vessels but is prevalent in medial vascular smooth muscle cells (VSMCs) from aged individuals and in atherosclerotic lesions, where it often colocalizes with senescent and degenerate VSMCs. Prelamin-A/C expression increases with age and disease. In normal aging, the accumulation of prelamin-A/C is caused in part by the down-regulation of ZMPSTE24/FACE1 in response to oxidative stress. {ECO:0000269PubMed:20458013}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 247 experimentally validated interaction(s) in this database.
They are also associated with 55 interaction(s) predicted by orthology.

Experimentally validated
Total	247 [view]
Protein-Protein	239 [view]
Protein-DNA	8 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	55 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0005198	structural molecule activity
GO:0005515	protein binding

Biological Process

GO:0000278	mitotic cell cycle
GO:0006915	apoptotic process
GO:0006921	cellular component disassembly involved in execution phase of apoptosis
GO:0006987	activation of signaling protein activity involved in unfolded protein response
GO:0006997	nucleus organization
GO:0006998	nuclear envelope organization
GO:0007077	mitotic nuclear envelope disassembly
GO:0007084	mitotic nuclear envelope reassembly
GO:0007517	muscle organ development
GO:0030334	regulation of cell migration
GO:0030951	establishment or maintenance of microtubule cytoskeleton polarity
GO:0030968	endoplasmic reticulum unfolded protein response
GO:0034504	protein localization to nucleus
GO:0035105	sterol regulatory element binding protein import into nucleus
GO:0044267	cellular protein metabolic process
GO:0055015	ventricular cardiac muscle cell development
GO:0071456	cellular response to hypoxia
GO:0090201	negative regulation of release of cytochrome c from mitochondria
GO:0090343	positive regulation of cell aging
GO:1900180	regulation of protein localization to nucleus
GO:2001237	negative regulation of extrinsic apoptotic signaling pathway

Cellular Component

GO:0005634	nucleus
GO:0005635	nuclear envelope
GO:0005638	lamin filament
GO:0005652	nuclear lamina
GO:0005654	nucleoplasm
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005882	intermediate filament
GO:0016607	nuclear speck
GO:0048471	perinuclear region of cytoplasm