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FLASH GENE

Symbol

LMNA

contributors: mct/ - updated : 05-03-2013

HGNC name	lamin A/C
HGNC id	6636

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_170707 12 - 3243 NP_733821 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 NM_005572 10 splicing 2077 NP_005563 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 NM_170708 11 splicing 3153 NP_733822 70.8 634 - 2008 18381888 lamin Adelta10 isoform, or variant 3 isoform 3 lacking an interval sequence progerin - - 2257 isoform 4 - 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)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart         Digestive esophagus       highly Endocrine adrenal gland       highly   pancreas         Nervous brain         Respiratory respiratory tract trachea     highly Skin/Tegument skin       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine

cells

System Cell Pubmed Species Stage Rna 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

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

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)
	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

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed miscelleaneous senescence   correction of cellular phenotypes of Hutchinson-Gilford Progeria cells by RNA interference, as potential gene therapy neuromuscular myopathy   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 osteoarticular bone   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 miscelleaneous senescence   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
	Lmna(-/-) mice display multiple tissue defects and die by 6-8 weeks of age reportedly from dilated cardiomyopathy with associated conduction defects