CD40LG (CD40 ligand)

Gene

• Entrez ID: 959
• Gene name: CD40 ligand
• Gene symbol: CD40LG
• Synonyms: CD154, CD40L, HIGM1, IGM, IMD3, T-BAM, TNFSF5, TRAP, gp39, hCD40L
• Chromosome: X
• Chromosome location: Xq26.3
• Summary: The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome. [provided by RefSeq, Jul 2008]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs104894768	G>T	Pathogenic	Coding sequence variant, missense variant
rs104894769	T>A,C	Pathogenic, likely-pathogenic	Coding sequence variant, missense variant
rs104894771	G>C	Pathogenic	Coding sequence variant, missense variant
rs104894772	A>G	Pathogenic	Coding sequence variant, missense variant
rs104894773	T>A,C	Likely-benign, pathogenic	Coding sequence variant, synonymous variant, missense variant
rs104894774	T>A,G	Likely-pathogenic	Coding sequence variant, missense variant
rs104894775	G>A	Pathogenic	Coding sequence variant, stop gained
rs104894777	T>G	Pathogenic, likely-pathogenic	Coding sequence variant, missense variant
rs104894778	C>A,T	Pathogenic, uncertain-significance	Coding sequence variant, missense variant
rs193922134	T>-	Likely-pathogenic	Frameshift variant, coding sequence variant
rs193922135	C>T	Pathogenic	Coding sequence variant, stop gained
rs193922136	C>A,T	Likely-pathogenic, pathogenic	Missense variant, coding sequence variant
rs368003929	C>T	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Missense variant, coding sequence variant
rs786205606	A>G	Likely-pathogenic	Missense variant, coding sequence variant
rs786205607	AT>-	Likely-pathogenic	Frameshift variant, coding sequence variant
rs886039326	G>A	Likely-pathogenic	Missense variant, coding sequence variant
rs886041747	G>-	Pathogenic	Frameshift variant, coding sequence variant
rs1057518628	C>-	Likely-pathogenic	Frameshift variant, coding sequence variant
rs1057521127	C>A	Likely-pathogenic, uncertain-significance	Missense variant, coding sequence variant
rs1057521128	T>C	Likely-pathogenic	Missense variant, coding sequence variant
rs1085307733	C>T	Pathogenic	Coding sequence variant, stop gained
rs1387503550	G>A,C	Pathogenic	Coding sequence variant, missense variant
rs1556136635	C>A	Pathogenic	Stop gained, coding sequence variant
rs1556139575	G>-	Pathogenic	Coding sequence variant, splice donor variant
rs1556143529	G>-	Pathogenic	Frameshift variant, coding sequence variant
rs1569376229	G>A	Likely-pathogenic	Splice donor variant
rs1569376925	AAAGAGGAGAC>-	Pathogenic	Coding sequence variant, frameshift variant
rs1569376930	GAAA>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1569377237	A>G	Pathogenic	Splice acceptor variant
rs1569377829	C>A	Likely-pathogenic	Coding sequence variant, missense variant
rs1569377865	T>C	Likely-pathogenic	Coding sequence variant, missense variant
rs1603319726	CA>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1603321138	C>-	Pathogenic	Coding sequence variant, frameshift variant
rs1603321154	T>-	Likely-pathogenic	Coding sequence variant, frameshift variant
rs1603321772	C>T	Likely-pathogenic	Coding sequence variant, stop gained
rs1603321834	C>T	Likely-pathogenic	Coding sequence variant, stop gained
rs1603321840	G>A	Likely-pathogenic	Coding sequence variant, missense variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT005463	hsa-miR-146a-5p	ELISA, Luciferase reporter assay, qRT-PCR, Western blot	21236257
MIRT619107	hsa-miR-4665-5p	HITS-CLIP	23824327
MIRT619108	hsa-miR-1275	HITS-CLIP	23824327
MIRT619109	hsa-miR-5010-5p	HITS-CLIP	23824327
MIRT619110	hsa-miR-4525	HITS-CLIP	23824327
MIRT619111	hsa-miR-7111-5p	HITS-CLIP	23824327
MIRT619112	hsa-miR-6870-5p	HITS-CLIP	23824327
MIRT619113	hsa-miR-5698	HITS-CLIP	23824327
MIRT619114	hsa-miR-4723-5p	HITS-CLIP	23824327
MIRT619115	hsa-miR-625-5p	HITS-CLIP	23824327
MIRT619116	hsa-miR-6825-5p	HITS-CLIP	23824327
MIRT619117	hsa-miR-6883-5p	HITS-CLIP	23824327
MIRT619118	hsa-miR-6785-5p	HITS-CLIP	23824327
MIRT619119	hsa-miR-4728-5p	HITS-CLIP	23824327
MIRT619120	hsa-miR-149-3p	HITS-CLIP	23824327
MIRT619121	hsa-miR-6797-5p	HITS-CLIP	23824327
MIRT619122	hsa-miR-1249-5p	HITS-CLIP	23824327
MIRT619123	hsa-miR-6077	HITS-CLIP	23824327
MIRT619124	hsa-miR-873-3p	HITS-CLIP	23824327
MIRT619125	hsa-miR-6855-3p	HITS-CLIP	23824327
MIRT619126	hsa-miR-4513	HITS-CLIP	23824327
MIRT619127	hsa-miR-637	HITS-CLIP	23824327
MIRT619128	hsa-miR-9500	HITS-CLIP	23824327
MIRT619129	hsa-miR-4499	HITS-CLIP	23824327
MIRT619130	hsa-miR-888-3p	HITS-CLIP	23824327
MIRT663020	hsa-miR-574-5p	HITS-CLIP	23824327
MIRT663020	hsa-miR-574-5p	HITS-CLIP	27418678
MIRT663021	hsa-miR-4455	HITS-CLIP	23824327
MIRT663022	hsa-miR-3152-3p	HITS-CLIP	23824327
MIRT663023	hsa-miR-6867-5p	HITS-CLIP	23824327
MIRT663023	hsa-miR-6867-5p	HITS-CLIP	27418678
MIRT663024	hsa-miR-5681a	HITS-CLIP	23824327
MIRT733981	hsa-miR-34a-5p	PCR array	28097098
MIRT784903	hsa-miR-345-5p	HITS-CLIP	27418678
MIRT785073	hsa-miR-3664-5p	HITS-CLIP	27418678
MIRT786094	hsa-miR-4522	HITS-CLIP	27418678

Transcription factors

Transcription factor	Regulation	Reference
FOS	Unknown	11160303
GATA3	Activation	18719603
JUND	Unknown	11160303
NFKB1	Activation	11751888
NFKB1	Unknown	11160303;11529914;21243522
REL	Unknown	11160303
RELA	Unknown	11160303;11529914;21243522
STAT1	Activation	12855573

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0002637	Process	Regulation of immunoglobulin production	IEA
GO:0005125	Function	Cytokine activity	IEA
GO:0005164	Function	Tumor necrosis factor receptor binding	IEA
GO:0005174	Function	CD40 receptor binding	IBA	21873635
GO:0005174	Function	CD40 receptor binding	IMP	31331973
GO:0005174	Function	CD40 receptor binding	IPI	9468137
GO:0005178	Function	Integrin binding	IMP	31331973
GO:0005515	Function	Protein binding	IPI	15067037, 31331973
GO:0005615	Component	Extracellular space	IEA
GO:0005886	Component	Plasma membrane	TAS
GO:0005887	Component	Integral component of plasma membrane	TAS	7678552
GO:0006954	Process	Inflammatory response	IDA	9468137
GO:0007159	Process	Leukocyte cell-cell adhesion	NAS	9468137
GO:0007229	Process	Integrin-mediated signaling pathway	IMP	31331973
GO:0007257	Process	Activation of JUN kinase activity	IDA	15067037
GO:0009897	Component	External side of plasma membrane	IEA
GO:0009986	Component	Cell surface	IDA	15067037
GO:0016021	Component	Integral component of membrane	NAS	9468137
GO:0023035	Process	CD40 signaling pathway	IMP	31331973
GO:0030168	Process	Platelet activation	IDA	9468137
GO:0030183	Process	B cell differentiation	IEA
GO:0031295	Process	T cell costimulation	TAS	8617933
GO:0032733	Process	Positive regulation of interleukin-10 production	IDA	8617933
GO:0032735	Process	Positive regulation of interleukin-12 production	IDA	9922218
GO:0032753	Process	Positive regulation of interleukin-4 production	IDA	8617933
GO:0033209	Process	Tumor necrosis factor-mediated signaling pathway	TAS
GO:0042100	Process	B cell proliferation	IDA	8605945
GO:0042102	Process	Positive regulation of T cell proliferation	IDA	8617933
GO:0043066	Process	Negative regulation of apoptotic process	IDA	12697681
GO:0045190	Process	Isotype switching	ISS
GO:0050776	Process	Regulation of immune response	TAS
GO:0051092	Process	Positive regulation of NF-kappaB transcription factor activity	IDA	15067037
GO:2000353	Process	Positive regulation of endothelial cell apoptotic process	IDA	12885753

Other IDs

• MIM: 300386
• HGNC: 11935
• e!Ensembl: ENSG00000102245

Protein

• UniProt ID: P29965
• Protein name: CD40 ligand (CD40-L) (T-cell antigen Gp39) (TNF-related activation protein) (TRAP) (Tumor necrosis factor ligand superfamily member 5) (CD antigen CD154) [Cleaved into: CD40 ligand, membrane form; CD40 ligand, soluble form (sCD40L)]
• Protein function: Cytokine that acts as a ligand to CD40/TNFRSF5 (PubMed:1280226, PubMed:31331973). Costimulates T-cell proliferation and cytokine production (PubMed:8617933). Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation (PubMed:8617933). Induces the activation of NF-kappa-B (PubMed:15067037, PubMed:31331973). Induces the activation of kinases MAPK8 and PAK2 in T-cells (PubMed:15067037). Induces tyrosine phosphorylation of isoform 3 of CD28 (PubMed:15067037). Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL4 (By similarity). Involved in immunoglobulin class switching (By similarity). ; [CD40 ligand, soluble form]: Acts as a ligand for integrins, specifically ITGA5:ITGB1 and ITGAV:ITGB3; both integrins and the CD40 receptor are required for activation of CD40-CD40LG signaling, which have cell-type dependent effects, such as B-cell activation, NF-kappa-B signaling and anti-apoptotic signaling.
• PDB: 1ALY, 1I9R, 3LKJ, 3QD6, 6BRB, 6W9G
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00229	TNF	138 → 261	TNF(Tumour Necrosis Factor) family	Domain

• Sequence:

  MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLH
  EDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKENSFEMQKGDQNP
  QIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSN
  REASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVN
  VTDPSQVSHGTGFTSFGLLKL

• Sequence length: 261

Pathways

KEGG:

Cytokine-cytokine receptor interaction
NF-kappa B signaling pathway
Cell adhesion molecules
T cell receptor signaling pathway
Intestinal immune network for IgA production
Malaria
Toxoplasmosis
Asthma
Autoimmune thyroid disease
Systemic lupus erythematosus
Allograft rejection
Primary immunodeficiency
Viral myocarditis
Lipid and atherosclerosis

Reactome:

Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
TNFR2 non-canonical NF-kB pathway
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway

Associated diseases

Causal
Disease name	Disease term	dbSNP ID	References
Anemia	Anemia, Hemolytic	rs118204044, rs118204045, rs118204046, rs121918330, rs869320719, rs869312029, rs121918332, rs869320724, rs767094129, rs786205058, rs786205059, rs137853119, rs137853120, rs137853121, rs1384933966, rs137853122, rs137853123, rs786205060, rs267607121, rs121908584, rs80338697, rs80338699, rs120074166, rs120074167, rs1050828, rs74575103, rs137852314, rs5030868, rs137852316, rs137852317, rs137852318, rs137852319, rs137852320, rs137852321, rs137852322, rs137852323, rs137852324, rs72554665, rs387906468, rs5030872, rs137852326, rs137852333, rs137852327, rs137852328, rs137852329, rs137852330, rs137852331, rs137852332, rs137852334, rs137852335, rs137852336, rs137852339, rs76645461, rs137852340, rs137852341, rs78478128, rs137852343, rs137852344, rs137852345, rs587776730, rs137852346, rs137852347, rs137852349, rs2070404412, rs2070350038, rs2070350009, rs137852303, rs137852304, rs33946267, rs34378160, rs33933298, rs11549407, rs35724775, rs34598529, rs41469945, rs267607201, rs80338694, rs80338696, rs387907018, rs398123546, rs78365220, rs587777100, rs587777101, rs483352840, rs869312752, rs765487627, rs1557229599, rs1557230040, rs1555524842, rs782090947, rs1358275550, rs1557229736, rs1557230573, rs1556323334, rs1233124208, rs1293528130, rs146864395, rs1595503440, rs1603411214, rs137852325, rs1575247302, rs1603411177, rs1336651679, rs782322505
Autoimmune diseases	Autoimmune Diseases	rs41285370, rs869025224	15494542
Amyotrophic lateral sclerosis	Amyotrophic Lateral Sclerosis, Amyotrophic Lateral Sclerosis, Guam Form	rs267607084, rs312262720, rs312262752, rs121908287, rs121908288, rs29001584, rs28941475, rs121434378, rs386134173, rs386134174, rs80356730, rs80356727, rs4884357, rs80356717, rs80356733, rs80356731, rs80356726, rs-1, rs267606928, rs267606929, rs1885090126, rs121434591, rs121912431, rs121912432, rs121912433, rs121912434, rs121912435, rs121912440, rs121912436, rs121912437, rs121912438, rs121912439, rs74315452, rs121912442, rs121912443, rs121912444, rs121912446, rs121912447, rs1197141604, rs121912448, rs121912449, rs121912450, rs121912451, rs121912452, rs121912453, rs121912454, rs369600566, rs121912455, rs121912456, rs121912457, rs121912458, rs1555836889, rs121909667, rs121909668, rs121909669, rs121909671, rs121909535, rs121909537, rs121909538, rs121909539, rs121909540, rs121909542, rs121909544, rs80356734, rs367543041, rs80356740, rs80356719, rs80356721, rs80356723, rs80356725, rs387906627, rs387906628, rs387906709, rs387906710, rs387906711, rs387906829, rs387907264, rs387907265, rs387907266, rs312262739, rs312262709, rs312262749, rs200793464, rs147713329, rs312262788, rs397514262, rs63751180, rs587777132, rs730880025, rs730880026, rs730880027, rs368743618, rs730880029, rs730882255, rs730882256, rs786205611, rs121912441, rs199947197, rs780136067, rs772731615, rs879253926, rs879254294, rs764717219, rs886041390, rs750159428, rs753207473, rs267607087, rs767350733, rs778305085, rs1554707680, rs1554707622, rs1393363759, rs750959420, rs1555509569, rs1554716504, rs11556620, rs1247392012, rs142083484, rs140385286, rs749428135, rs371575563, rs1402429085, rs1218712729, rs1555179091, rs1555179087, rs746971952, rs1555836950, rs368276916, rs140376902, rs747220413, rs76731700, rs770684782, rs1200906022, rs1804449, rs1482760341, rs769898852, rs140599944, rs757972700, rs1555451521, rs1592362719, rs1555836803, rs763455928, rs1378590183, rs1583695322, rs1362178149, rs1197928094, rs368751524, rs1555509609, rs1574787779, rs1601157750, rs1301635320, rs1341055534, rs1402092579, rs1568809172, rs1555836170, rs1315541036, rs1339283341, rs1643659556, rs1644506661, rs1435710212, rs1553122918, rs1689580631, rs374047961, rs775935265, rs2076486420, rs1820836522, rs757260058, rs1844420892, rs1833371664, rs1833438306, rs1833451208, rs2083790483, rs1303294230, rs1226110412, rs2053207945, rs2053208751, rs2053501632, rs2053539304, rs1567479067, rs544088874, rs1228194239, rs1568807400, rs1169198442, rs2049594204, rs2049594311, rs1568810641, rs1568811372, rs2049618449, rs1476760624, rs2079347087	20348957
Coronary artery disease	Coronary Artery Disease	rs137852988, rs121918313, rs-1, rs121918529, rs121918531, rs137852340, rs405509, rs1555800701, rs1215189537	16368305
Neutropenia	Neutropenia	rs879253882

Unknown
Disease name	Disease term	dbSNP ID	References
Hyperimmunoglobulin m syndrome	Hyperimmunoglobulin M syndrome	rs200602841, rs5796316, rs56185014, rs780337127, rs201738977, rs755095913, rs746182207, rs886056721, rs749590513, rs886056719, rs11569300, rs1345004	24402618, 19575287, 17351759
Amyotrophic lateral sclerosis with dementia	Amyotrophic Lateral Sclerosis With Dementia		20348957
Coronary arteriosclerosis	Coronary Arteriosclerosis		16368305
Dysgammaglobulinemia	Dysgammaglobulinemia
Gingivitis	Gingivitis
Hyper-igm immunodeficiency syndrome	Hyper-IgM Immunodeficiency Syndrome, Type 1		10484640, 17351759, 7679206, 7678782, 7717401, 9746782, 15611226, 25541662, 7916370, 15623492, 27189378, 9150729, 31331973, 15924140, 7679801, 19575287, 8889581, 8094231, 8550833, 22678466, 7532185, 20591076, 15358621, 1427881, 26545377, 29077208
Hyper-igm syndrome, x-linked	X-linked hyper-IgM syndrome
Hypertrophy of tonsils	Hypertrophy of tonsils
Immunologic deficiency syndromes	Immunologic Deficiency Syndromes
Stomatitis	Stomatitis