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FLASH GENE

Symbol

CTLA4

contributors: mct/shn - updated : 15-12-2015

HGNC name	cytotoxic T-lymphocyte-associated protein 4
HGNC id	2505

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	GD5S Graves disease, susceptibility locus 5
Location	2q33.2      Physical location : 204.732.508 - 204.738.683
Synonym name	celiac disease 3
	cell differentiation antigen CD152
	cytotoxic T-lymphocyte-associated granule serine protease 4
	ligand and transmembrane spliced cytotoxic T lymphocyte associated antigen 4
	cytotoxic T-lymphocyte-associated antigen 4
	cytotoxic T-lymphocyte-associated serine esterase-4
	ligand and transmembrane spliced cytotoxic T lymphocyte associated antigen 4
	cytotoxic T-lymphocyte antigen 4
	CD152 antigen
Synonym symbol(s)	CD152, CTLA-4, GSE, CD, CD28, ICOS, GRD4, CELIAC3
EC.number	3.4.21.-

DNA

TYPE	functioning gene
STRUCTURE	6.17 kb     4 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	cen - D2S1391 - D2S307 - CTLA4 - D2S72 - D2S105 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005214 4 splicing 1988 NP_005205 - 223 - 2007 17197413 also called CTLA4-TM NM_001037631 3 splicing 1878 NP_001032720 - 174 - 2007 17197413 also called CTLA-4delTM variant S-CTLA4 - splicing 214 isoform S-CTLA4 - 58 - 2008 18595775 lower expression of S-CTLA4 mRNA relative to the membrane form in myasthenia gravis patients variant L-CTLA4 - splicing 277 isoform L-CTLA4 - 79 - 2008 18595775 more prevalent in myasthenia gravis patients compared to healthy controls

EXPRESSION

Type	restricted

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 Lymphoid/Immune thymus cortex       Homo sapiens Reproductive male system prostate       Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune activated B lymphocyte

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES		Hydrophobic
STRUCTURE

motifs/domains	hydrophobic transmembrane region of 37AA
	two Ig extracellular domains
	a long cytoplasmic tail, with two tyrosine based inhibitory motifs (ITIM)

conjugated

PhosphoP

isoforms

Precursor

HOMOLOGY

interspecies	ortholog to Ctla4, Mus musculus
	ortholog to Ctla4, Rattus norvegicus
	ortholog to CTLA4, Pan troglodytes

intraspecies

homolog to CD28

Homologene

FAMILY

inducible costimulator family (CD28 gene family)

CATEGORY

immunity/defense , receptor

SUBCELLULAR LOCALIZATION

plasma membrane

basic FUNCTION	B7 costimulatory protein receptor for CD80, CD86, negative regulatory T cell presenting costimulatory molecule
	expressed on activated T lymphocytes and involved in down-regulation of the immune response
	has a critical role in T cell differentiation (
	plays an inhibitory role in the immune response and has been suggested to be involved in the pathophysiology of myasthenia gravis
	acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands
	functions potentially in a T cell-extrinsic manner
	is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease
	regulates the early development of self-reactive T cells in the thymus and plays a key role in central tolerance
	in the thymus, works together with other signals to set the required level of TCR avidity and determine the development of both Tconv and Treg cells

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

disulfide-linked homodimer of CTLA4 and CD86 (B7.2)

INTERACTION

DNA

RNA

small molecule

protein	CD28, B7-1 and early T cell costimulatory molecule, ETC-1 (
	phosphatidylinositol 3-kinase, PI 3-kinase (
	the tyrosine phosphatase SYP (
	Lyn, Lck and SHP-2 (
	Janus Kinase 2, Jak2 (
	medium chain mu 2 subunit, AP50 (
	CD80 (
	CD80 and CD86 (
	signal transducer and activator of transcription 5, STAT5 (
	PPP2R4
	ICOSLG-CD28 interaction was essential for the costimulation of human T cells primary responses to allogeneic antigens and memory recall responses
	RGMB binds an extracellular domain of CTLA4, and specifically strengthens the binding of the monomeric, soluble form of CTLA4 (sCTLA-4) to CD80

cell & other

REGULATION

repressed by

subunit of the serine/threonine phosphatase 2A, PP2A (

ASSOCIATED DISORDERS

corresponding disease(s)

GD5S

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --other   aberrant expressions of endometrial ID3 and CTLA4 are associated with unexplained repeated implantation failure and recurrent miscarriage

Susceptibility

to celiac disease ( to multiple sclerosis to Graves disease ( to Hashimoto thyroiditis and Addison's disease (PubMed:9398726) to diabetes mellitus ( to thyroid associated orbitopathy to rheumatoid arthritis(RA) to multiple sclerosis to systemic lupus erythematosus( to Addison disease to non-Hodgkin's lymphoma (NHL) to Vogt-Koyanagi-Harada to dilated cardiomyopathy (DCM) to myasthenia gravis ( to hepatitis B virus clearance and persistence (

Variant & Polymorphism SNP , other	exon 3 microsatellite, 106 bp allele conferring susceptibility to Graves disease and to thyroid associated orbitopathy (see also IDDM12)
	49A>G increasing the risk of celiac disease and of multiple sclerosis with secondary progressive form
	allele +49 and CT60 increasing the risk of RA
	strong association of the CTLA4 49A and the 3'-untranslated region (AT)(82) alleles with NHL
	polymorphisms associated with the susceptibility to VKH syndrome(Vogt-Koyanagi-Harada)
	common variant, Thr17Ala, confers susceptibility for DCM, but does not seem to influence the course of the disease 1 year after diagnosis

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed immunology autoimmune   a potential therapeutic target in the prevention of autoimmune endocrine disorders

ANIMAL & CELL MODELS

	lymph nodes and spleens of CTLA4-deficient mice accumulate T cell blasts which infiltrate liver, heart, lung, and pancreas tissue, and amounts of serum immunoglobulin are elevated leading to early lethality (
	CTLA-4(-/-) T cells from CTLA-4(-/-) mice have a diverse and unbiased TCR repertoire (
	specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell-mediated autoimmune disease, and hyperproduction of immunoglobulin E in mice, and it also produces potent tumor immunity (