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FLASH GENE
Symbol LMNA contributors: mct/ - updated : 05-03-2013
HGNC name lamin A/C
HGNC id 6636
Corresponding disease
CMD1A cardiomyopathy, dilated 1A
CMT2B1 Charcot-Marie-Tooth disease, axonal, type 2B1
EMD2 Emery-Dreifuss muscular dystrophy 2
EMD3 Emery-Dreifuss muscular dystrophy 3
FPLD2 familial partial lipodystrophy
HHSS heart hand syndrome, Slovenian type
LDHCP lipoatrophy with diabetes, hepatic steatosis, hypertrophic cardiomyopathy and leukomelanodermic papules
LGMD1B limb girdle muscular dystrophy 1B
MADYS1 mandibuloacral dysplasia
MCPRS myopathy and cutaneous progeria syndrome
PRO1 Hutchinson-Gilford progeria syndrome
RDMP2 restrictive dermopathy, lethal 2
WRN2 Werner syndrome 2
Location 1q22      Physical location : 156.084.460 - 156.109.878
Synonym name
  • progerin
  • 70 kDa lamin
  • renal carcinoma antigen NY-REN-32
  • lamin A/C-like 1
  • Synonym symbol(s) LMN1, FPL, LDP, LB3T, LMNB3, IDC, CDDC, FPLD, HGPS, LDP1, LMNC, CDCD1
    DNA
    TYPE functioning gene
    STRUCTURE 25.42 kb     12 Exon(s)
    Genomic sequence alignment details
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter (CAAT box) (TATA box)
    text structure
  • binding sites for SREBF1, SREBF2
  • a retinoic acid-responsive element in the LMNA promoter that is regulated by the transcription factors c-Jun and Sp1/Sp3
  • also other regulatory motifs in the LMNA promoter binding the transcription factors Sp1/3, c-Jun, and c-Fos, and the transcriptional coactivator CREB-binding protein
  • MAPPING cloned Y linked N status confirmed
    Map cen - D1S3757 - [D1S2346 - D1S2715 - NPR1 - DAP3 - D1S303 - D1S2777 - SCAMP3 - MUC1 - D1S2714 - D1S2140 - LMNA - D1S2721 - D1S2624 ] - D1S506 - INSRR - FGFR2 - qter
    Authors Shackleton (00)
    Text [FPL ]
    Physical map
    LOC284620 1q22 similar to CLDN6 MRPS29P1 1q21.3 mitochondrial ribosomal protein S29 pseudogene 1 FLJ10504 1q22 misato YAP 1q21.3 misato DAP3 1q21 death associated protein 3 LOC388705 1 similar to misato FLJ20203 1q22 hypothetical protein FLJ20203 SYT11 1q21.2 synaptotagmin XI RIT1 1q21.2 Ras-like without CAAX 1 KIAA0907 1q21 Ras-like without CAAX 1 GPR100 1q22 G protein-coupled receptor 100 ARHGEF2 1q11-q21 rho/rac guanine nucleotide exchange factor (GEF) 2 SSR2 1q21-q23 signal sequence receptor, beta (translocon-associated protein beta) C1orf6 1q21 chromosome 1 open reading Frame 6 MAPBPIP 1q22 mitogen-activated protein-binding protein-interacting protein RAB25 1q21.2 RAB25, member RAS oncogene family LOC92312 1q22-q23.1 hypothetical protein LOC92312 LMNA 1q21.2-q21.3 lamin A/C FLJ12287 1q22 hypothetical protein FLJ12287 similar to semaphorins LOC388706 1 LOC388706 KIAA0446 1q23.1 KIAA0446 gene product PMF1 1q12-q21.1 polyamine-modulated factor 1 BGLAP 1q25-q31 bone gamma-carboxyglutamate (gla) protein (osteocalcin) PAQR6 1q23.1 progestin and adipoQ receptor family member VI EST1B 1q21.2 Est1p-like protein B MGC13102 1q23.1 hypothetical protein MGC13102 MGC31963 1q23.1 kidney predominant protein NCU-G1 LOC391104 1 similar to Von Hippel-Lindau disease tumor suppressor (pVHL) (G7 protein) CCT3 1q23 chaperonin containing TCP1, subunit 3 (gamma) SSTK-IP 1q23.1 SSTK-interacting protein RHBG 1q21.3 Rhesus blood group, B glycoprotein CROC4 1q12-q25 Rhesus blood group, B glycoprotein MEF2D 1q12-q23 MADS box transcription enhancer factor 2, polypeptide D (myocyte enhancer factor 2D) IQGAP3 1q21.3 IQ motif containing GTPase activating protein 3 LOC164118 1q23.1 similar to RIKEN cDNA A430025D11 APOA1BP 1q21.2 apolipoprotein A-I binding protein FLJ20249 1q22 hypothetical protein FLJ20249 BRAL1 1q22 hypothetical protein FLJ20249 BCAN 1q23-q31 hypothetical protein FLJ20249 NES 1q23.1 nestin CRABP2 1q21.3 cellular retinoic acid binding protein 2 FLJ12671 1q23.1 hypothetical protein FLJ12671 CGI-41 1q23.1 CGI-41 protein MRPL24 1q21-q22 mitochondrial ribosomal protein L24 HDGF Xq25 hepatoma-derived growth factor (high-mobility group protein 1-like)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    12 - 3243 74.1 664 - 2008 18381888
  • lamin A, or variant 1 isoform 1
  • associates with chromatin both directly and indirectly and has been suggested to play important roles in chromatin organization, transcription, DNA replication, and apoptosis
  • 10 splicing 2077 65.2 572 - 2008 18381888
  • lamin C or variant 2 Isoform 2
  • an alternative splice site in the 3' coding region resulting in a distinct C terminus
  • 11 splicing 3153 70.8 634 - 2008 18381888
  • lamin Adelta10 isoform, or variant 3 isoform 3
  • lacking an interval sequence
  • - - 2257 - 614 - 2007 17360355
  • progerin/LADelta50
  • 50-AA deletion within its C terminus (deletion from the C-terminal tail, AA 607–656)
  • lacking the normal cleavage site to remove a C-terminal farnesyl group
  • during interphase, irreversibly farnesylated progerin/LADelta50 anchors to the nuclear membrane and causes characteristic nuclear blebbing
  • mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation
  • DNA/chromatin binding properties of the progerin tail are distinct from those of wild-type A-type and B-type lamin tails, and has a reduced DNA/chromatin binding capacity and modified trimethylated H3K27 binding pattern (PMID: 20580717)
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Digestiveesophagus   highly
    Endocrineadrenal gland   highly
     pancreas    
    Nervousbrain    
    Respiratoryrespiratory tracttrachea  highly
    Skin/Tegumentskin   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
     differentiated cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • an N terminal globular head domain
  • a central rod domain (alpha-helical rod domain) , responsible for the formation of in-parallel and in-register coiled-coil dimers, the building blocks of lamin polymers
  • a nuclear localization signal (NLS)
  • an Ig fold domain
  • AA stretch (aa 607–646) of lamin A constitutes a binding site for DNA and chromatin
  • a C terminal globular tail domain including a CAAX prenylation motif in prelamin A, cleaved in the lamin A and a DNA binding domain, a signal for posttranslational farnesylation by the farnesyltransferase enzyme
  • conjugated FlavoP
    mono polymer homomer , heteromer , dimer , tetramer
    isoforms Precursor of two alternatively spliced isoforms A et C, converted in mature form LMNA after isoprenylation of CAAX box and incorporation into the lamina structure
    HOMOLOGY
    interspecies ortholog to rattus Lmna (85.5pc)
    ortholog to murine Lmna (96.5pc)
    ortholog to zebrafish lmna (76.1pc)
    Homologene
    FAMILY
  • intermediate filament family
  • CATEGORY structural protein
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytoskeleton,intermed filament
    intracellular,nucleus,nucleoplasm
    intracellular,nuclear envelope,int
    intracellular,nuclear envelope,lamina
    text
  • nuclear matrix, constituent of the inner nuclear membrane intermediate filament
  • SUN1 and LMNA colocalize at the Nuclear Envelope (NE)
  • detected predominantly in the nuclear rim
  • basic FUNCTION
  • mediating interactions with the nuclear envelope, and also tethering the nuclear envelope to chromatin
  • playing a major role in chromatin organization, DNA replication and RNA polymerase II-dependent gene expression
  • involved in nuclear stability, chromatin structure and gene expression
  • playing a key role in maintaining cellular resistance to deformation and in nucleo-cytoskeletal integrity
  • involved in the modulation of TGF-beta1 on collagen production, a marker of mesenchymal differentiation via nuclear phosphatases such as PPP2R3B
  • acting as inhibitors of adipocyte differentiation, possibly by affecting PPARgamma2 and insulin signaling
  • invovled in physiological aging
  • playing a critical role through the C-terminal globular lamin A/C region in nuclear structure (major contribution of abnormal assembly to the progeroid phenotype)
  • playing a role in normal cell senescence
  • involved in muscle differentiation
  • link between pre-lamin A processing and heterochromatin remodeling
  • SUMO modification is important for normal LMNA function and implicate an involvement for altered sumoylation in the E203G/E203K lamin A cardiomyopathies
  • importance of lamins in nuclear assembly and chromatin organization, and essential role in establishing and maintaining nuclear architecture
  • might have a role in normal physiological cellular senescence
  • LMNA and LBR sequentially tether peripheral heterochromatin and inversely regulate differentiation
  • type V intermediate filament protein forming a filamentous meshwork, the lamina, underneath the inner nuclear membrane, for nuclear envelope structures organization and interphase chromatin anchoring
  • component of the nuclear lamina that plays a critical role in the structural organization and function of the nucleus
  • CELLULAR PROCESS nucleotide, chromatin organization
    nucleotide, transcription, regulation
    cell organization/biogenesis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • constituent of the inner nuclear membrane intermediate filament
  • part of LINC complex
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • SREBF1 (retention of SREBF1 by LMNA, causing down-regulation of PPARG expression and reducing the rate of preadipocytes differentiation) and SREBF2
  • TRAF3
  • EMD
  • interacting with the nuclear actin
  • interacting with RB, MADH2, PPP2R3B (crucial interaction for proper regulation of mesenchymal cellular physiology)
  • binding to CCND3
  • interacts with D41Z4 (Lamins A/C are involved in the anti-silencing activity of D4Z4 and uncovers the involvement of both CTCF and A-type Lamins in the regulation of an insulator in human cells)
  • molecularly connected with EMD (emerin-prelamin A interplay influences nuclear organization)
  • nucleoporin NUP88 is interacting with nuclear lamin A
  • interacting with MLIP (interaction domain is between AAs 1 and 130 of LMNA, which includes the N-terminal globular head domain plus coil 1A, linker 1, and the first 43 AAs of coil 1B)
  • LMNA splicing regulation by the SR proteins SRSF1 and SRSF6
  • interaction between accumulated preLMNA and SP1 transcription factor, results in altered extracellular matrix gene expression, impairing adipogenesis
  • AKT1 regulates LMNA transcription, having a function in the control of prelamin A stability and expression
  • physical interaction between FAM96B and LMNA, which may provide some clues to the mechanisms of LMNA in premature aging, and interaction between the two proteins might give rise to the retention of FAM96B at the nuclear envelope
  • cell & other
    REGULATION
    Phosphorylated by AKT1 (AKT1 phosphorylation at S404 targets the precursor prelamin A for degradation)
    Other disassembly at the start and reassembly at the end of mitosis mediated by phosphorylation, dephosphorylation
    ASSOCIATED DISORDERS
    corresponding disease(s) EMD2 , LGMD1B , CMD1A , CMT2B1 , FPLD2 , MADYS1 , PRO1 , WRN2 , RDMP2 , LDHCP , EMD3 , MCPRS , HHSS
    related resource Limb-Girdle Muscular Dystrophy pages
    Mutation Database of Inherited Peripheral Neuropathies
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    by hypermethylation associated with poor outcome in diffuse large B-cell lymphomas
    constitutional germinal mutation      
    results in increased sensitivity to DNA damaging agents, an elevated DNA damage response, and a senescent phenotype
    constitutional       loss of function
    in striated muscle disease mutated proteins are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement
    tumoral     --low  
    silencing of A-type lamins by DNA methylation in some cancers could contribute to the genomic instability that drives malignancy
    constitutional germinal mutation      
    LMNA mutation should be considered in myopathy patients with inflammatory changes during infancy
    constitutional     --over  
    in osteoarthritis (OA) chondrocytes, and increased nuclear accumulation of LMNA in response to catabolic stress may account for the premature aging phenotype and apoptosis of OA chondrocytes
    Susceptibility
  • to subcutaneous abdominal abnormal adipocyte size
  • to metabolic syndrome and also higher mean fasting triglyceride and lower mean HDL-cholesterol concentrations
  • to enhanced longevity
  • Variant & Polymorphism SNP , other
  • 1908 C>T Pima Indians
  • H566H polymorphism associated with metabolic syndrome and also higher mean fasting triglyceride and lower mean HDL-cholesterol concentrations in the Old Order Amish
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    miscelleaneoussenescence 
    correction of cellular phenotypes of Hutchinson-Gilford Progeria cells by RNA interference, as potential gene therapy
    neuromuscularmyopathy 
    ERK inhibition as a therapeutic option to prevent or delay heart failure in Emery–Dreifuss muscular dystrophy and related disorders caused by mutations in LMNA
    osteoarticularbone 
    processing of prelamin A could become a new approach to regulate osteoblastogenesis and bone turnover and thus for the prevention and treatment of senile osteoporosis
    miscelleaneoussenescence 
    correction of the aberrant splicing event using a modified oligonucleotide targeted to the activated cryptic splice site (treatment inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome)
    cancer  
    lamins-deficient tumor cells could represent a good target for radiation therapy
    ANIMAL & CELL MODELS
  • abnormal activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) signaling cascade in hearts of Lmna H222P ‘knock in’ mice, a model of autosomal Emery–Dreifuss muscular dystrophy
  • changes in the splicing ratio between lamin A and progerin are key factors for lifespan since heterozygous mice harboring the mutation lived longer than homozygous littermates but less than the wild-type
  • Lmna(-/-) mice display multiple tissue defects and die by 6-8 weeks of age reportedly from dilated cardiomyopathy with associated conduction defects