DEDD2

Summary

DEDD2 (death effector domain containing 2, HGNC:24450) is a protein-coding gene on chromosome 19q13.2, encoding DNA-binding death effector domain-containing protein 2 (Q8WXF8). May play a critical role in death receptor-induced apoptosis and may target CASP8 and CASP10 to the nucleus.

This gene encodes a nuclear-localized protein containing a death effector domain (DED). The encoded protein may regulate the trafficking of caspases and other proteins into the nucleus during death receptor-induced apoptosis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 162989 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 67 total — 1 pathogenic
• MANE Select transcript: NM_133328

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24450
Approved symbol	DEDD2
Name	death effector domain containing 2
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLAME-3
Ensembl gene	ENSG00000160570
Ensembl biotype	protein_coding
OMIM	617078
Entrez	162989

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 14 protein_coding, 8 protein_coding_CDS_not_defined

ENST00000336034, ENST00000593561, ENST00000593804, ENST00000595337, ENST00000596251, ENST00000598090, ENST00000598200, ENST00000598415, ENST00000598727, ENST00000600559, ENST00000601135, ENST00000602075, ENST00000602201, ENST00000898287, ENST00000898288, ENST00000898289, ENST00000898290, ENST00000898291, ENST00000898292, ENST00000898293, ENST00000898294, ENST00000948092

RefSeq mRNA: 3 — MANE Select: NM_133328 NM_001270614, NM_001270615, NM_133328

CCDS: CCDS12597, CCDS59391

Canonical transcript exons

ENST00000596251 — 5 exons

Exon	Start	End
ENSE00001388416	42216680	42217045
ENSE00003177465	42198598	42199829
ENSE00003199563	42217632	42217677
ENSE00003557060	42209700	42209840
ENSE00003659576	42215133	42215252

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 96.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.9963 / max 987.8589, expressed in 1808 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181147	19.5851	1793
181149	2.3607	1354
181148	0.7544	490
181150	0.1807	53
181146	0.1153	38

Top tissues by expression

253 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.55	gold quality
blood	UBERON:0000178	96.34	gold quality
leukocyte	CL:0000738	94.86	gold quality
monocyte	CL:0000576	94.74	gold quality
amniotic fluid	UBERON:0000173	94.60	gold quality
ileal mucosa	UBERON:0000331	94.20	gold quality
bronchial epithelial cell	CL:0002328	93.47	gold quality
bronchus	UBERON:0002185	93.29	gold quality
nasal cavity epithelium	UBERON:0005384	93.26	gold quality
endothelial cell	CL:0000115	92.75	silver quality
left ventricle myocardium	UBERON:0006566	92.67	gold quality
bone marrow	UBERON:0002371	92.27	gold quality
pituitary gland	UBERON:0000007	91.53	gold quality
upper arm skin	UBERON:0004263	91.44	gold quality
bone marrow cell	CL:0002092	91.00	gold quality
adenohypophysis	UBERON:0002196	90.93	gold quality
cerebellar vermis	UBERON:0004720	90.88	gold quality
skin of leg	UBERON:0001511	90.83	gold quality
spleen	UBERON:0002106	90.47	gold quality
skin of abdomen	UBERON:0001416	90.21	gold quality
kidney epithelium	UBERON:0004819	90.08	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	90.07	gold quality
mucosa of transverse colon	UBERON:0004991	89.74	gold quality
zone of skin	UBERON:0000014	89.73	gold quality
prefrontal cortex	UBERON:0000451	89.51	gold quality
hypothalamus	UBERON:0001898	89.49	gold quality
thymus	UBERON:0002370	89.44	gold quality
mucosa of stomach	UBERON:0001199	89.38	gold quality
right frontal lobe	UBERON:0002810	89.30	gold quality
lower esophagus mucosa	UBERON:0035834	89.28	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

50 targeting DEDD2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-4710	98.61	65.96	1048

Literature-anchored findings (GeneRIF, showing 2)

• FLAME-3 forms nuclear complexes with the TFIIIC102 subunit of human transcription factor IIIC (PMID:11965497)
• DEDD and DEDD2 may be important mediators for death receptors and that they may target caspases to the nucleus. (PMID:12527898)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dedd1	ENSDARG00000002758
mus_musculus	Dedd2	ENSMUSG00000054499
rattus_norvegicus	Dedd2	ENSRNOG00000046112

Paralogs (1): DEDD (ENSG00000158796)

Protein

Protein identifiers

DNA-binding death effector domain-containing protein 2 — Q8WXF8 (reviewed: Q8WXF8)

Alternative names: DED-containing protein FLAME-3, FADD-like anti-apoptotic molecule 3

All UniProt accessions (3): Q8WXF8, M0QXK7, M0QYK9

UniProt curated annotations — full annotation on UniProt →

Function. May play a critical role in death receptor-induced apoptosis and may target CASP8 and CASP10 to the nucleus. May regulate degradation of intermediate filaments during apoptosis. May play a role in the general transcription machinery in the nucleus and might be an important regulator of the activity of GTF3C3.

Subunit / interactions. Interacts with CASP8, CASP10 and GTF3C3. Homodimerizes and heterodimerizes with DEDD.

Subcellular location. Nucleus. Nucleolus.

Tissue specificity. Expressed in most tissues. High levels were found in liver, kidney, heart, ovary, spleen, testes, skeletal muscle and peripheral blood leukocytes. Expression was absent or low in colon and small intestine. Expression is relatively high in the tumor cell lines chronic myologenous leukemia K-562 and the colorectal adenocarcinoma SW480. Expression is moderate in the cervical carcinoma HeLa, the Burkitt’s lymphoma Raji, the lung carcinoma A-549, and the melanoma G-361. In contrast, two leukemia cell lines, HL-60 (promyelocytic leukemia) and MOLT-4 (lymphoblastic leukemia), show relatively low levels.

Domain organisation. Interactions with CASP8 and CASP10 are mediated by the DED domain.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WXF8-1	1	yes
Q8WXF8-2	2

RefSeq proteins (3): NP_001257543, NP_001257544, NP_579874* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001875	DED_dom	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR038856	DEDD/DEDD2	Family
IPR049341	TRADD-like_N	Domain

Pfam: PF01335, PF20694

UniProt features (14 total): sequence conflict 5, compositionally biased region 3, short sequence motif 2, chain 1, domain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WXF8-F1	72.80	0.44

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-3371511	HSF1 activation
R-HSA-3371568	Attenuation phase
R-HSA-3371571	HSF1-dependent transactivation

MSigDB gene sets: 116 (showing top): PEREZ_TP63_TARGETS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_APOPTOTIC_SIGNALING_PATHWAY, KOYAMA_SEMA3B_TARGETS_UP, GOBP_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_VIA_DEATH_DOMAIN_RECEPTORS, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, PEREZ_TP53_AND_TP63_TARGETS, NOJIMA_SFRP2_TARGETS_UP, GOBP_RRNA_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_EXECUTION_PHASE_OF_APOPTOSIS

GO Biological Process (10): RNA processing (GO:0006396), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), rRNA catabolic process (GO:0016075), cellular homeostasis (GO:0019725), apoptotic nuclear changes (GO:0030262), intracellular signal transduction (GO:0035556), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), apoptotic process (GO:0006915), regulation of apoptotic process (GO:0042981)

GO Molecular Function (3): DNA binding (GO:0003677), signaling receptor complex adaptor activity (GO:0030159), protein binding (GO:0005515)

GO Cellular Component (3): nucleoplasm (GO:0005654), nucleolus (GO:0005730), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cellular response to heat stress	3
HSF1-dependent transactivation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
extrinsic apoptotic signaling pathway	2
nuclear lumen	2
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA catabolic process	1
rRNA metabolic process	1
homeostatic process	1
cellular component disassembly involved in execution phase of apoptosis	1
intracellular anatomical structure	1
signal transduction	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
apoptotic process	1
regulation of programmed cell death	1
nucleic acid binding	1
signaling receptor binding	1
signaling adaptor activity	1
binding	1
cellular anatomical structure	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DEDD2	KRT18	P05783	669
DEDD2	KRT8	P05787	668
DEDD2	FADD	Q13158	587
DEDD2	GTF3C3	Q9Y5Q9	584
DEDD2	CFLAR	O15519	580
DEDD2	CCAR1	Q8IX12	511
DEDD2	PRR19	A6NJB7	477
DEDD2	CMSS1	Q9BQ75	455
DEDD2	YPEL4	Q96NS1	445
DEDD2	MACO1	Q8N5G2	439
DEDD2	CASP3	P42574	409
DEDD2	ZNF526	Q8TF50	401
DEDD2	TMA16	Q96EY4	385
DEDD2	C3orf70	A6NLC5	376
DEDD2	KRTAP10-6	P60371	366

IntAct

9 interactions, top by confidence:

A	B	Type	Score
CDK6	DEDD2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
ATG16L1	DEDD2	psi-mi:“MI:0915”(physical association)	0.400
DEDD2	rep	psi-mi:“MI:0915”(physical association)	0.370
NR2E3	DEDD2	psi-mi:“MI:0915”(physical association)	0.370
RBFOX2	DEDD2	psi-mi:“MI:0915”(physical association)	0.370
HNRNPAB	DEDD2	psi-mi:“MI:0915”(physical association)	0.370
RHOXF2	DEDD2	psi-mi:“MI:0915”(physical association)	0.370
FMR1	DEDD2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (33): DEDD2 (Two-hybrid), DEDD2 (Proximity Label-MS), DEDD2 (Proximity Label-MS), DEDD2 (Two-hybrid), ATG16L1 (Reconstituted Complex), CFLAR (Reconstituted Complex), DEDD2 (Affinity Capture-Western), CFLAR (Affinity Capture-Western), DEDD (Affinity Capture-Western), CASP8 (Affinity Capture-Western), CASP8 (Reconstituted Complex), CFLAR (Reconstituted Complex), DEDD2 (Affinity Capture-Western), DEDD2 (Affinity Capture-Western), DEDD (Reconstituted Complex)

ESM2 similar proteins: A0A8I5KY20, A2A9T0, A2IDD5, B0BNK9, B8ZZ34, C9JI98, C9JLR9, F5GYI3, O18734, P0CG25, P84157, Q0IIA6, Q0PHV7, Q0X0E2, Q13387, Q1RMK9, Q2M3D2, Q2TAM9, Q3ZCQ3, Q4VA45, Q673H1, Q69YZ2, Q6NS60, Q6P6N5, Q6PJ61, Q7Z6J2, Q80ZJ8, Q810I0, Q86SX3, Q86UD0, Q86XT2, Q8BNN1, Q8IUW3, Q8N4Y2, Q8N6N2, Q8QZV0, Q8R4T5, Q8TF61, Q8VCR9, Q8WXF8

Diamond homologs: O75618, Q8QZV0, Q8WXF8, Q9Z1L3, Q9Z2K0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

67 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	57
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1064662	GRCh38/hg38 19q13.2(chr19:42198610-42249880)x1	Pathogenic

SpliceAI

1059 predictions. Top by Δscore:

Variant	Effect	Δscore
19:42199825:GATGT:G	acceptor_gain	1.0000
19:42199826:ATGT:A	acceptor_gain	1.0000
19:42199827:TGT:T	acceptor_gain	1.0000
19:42199828:GT:G	acceptor_gain	1.0000
19:42199828:GTC:G	acceptor_loss	1.0000
19:42199829:TCTGC:T	acceptor_loss	1.0000
19:42199830:C:CC	acceptor_gain	1.0000
19:42199830:CTGCA:C	acceptor_loss	1.0000
19:42215127:GCTCA:G	donor_loss	1.0000
19:42215128:CTCA:C	donor_loss	1.0000
19:42215129:TCA:T	donor_loss	1.0000
19:42215130:CA:C	donor_loss	1.0000
19:42215131:ACCT:A	donor_loss	1.0000
19:42215132:C:CT	donor_loss	1.0000
19:42215146:AC:A	donor_gain	1.0000
19:42215147:CC:C	donor_gain	1.0000
19:42215147:CCCTG:C	donor_gain	1.0000
19:42215248:AGACA:A	acceptor_gain	1.0000
19:42215249:GACA:G	acceptor_gain	1.0000
19:42215250:ACA:A	acceptor_gain	1.0000
19:42215251:CA:C	acceptor_gain	1.0000
19:42215251:CAC:C	acceptor_gain	1.0000
19:42215253:C:CC	acceptor_gain	1.0000
19:42216674:CCGTA:C	donor_loss	1.0000
19:42216675:CGTAC:C	donor_loss	1.0000
19:42216677:TAC:T	donor_loss	1.0000
19:42216679:C:CG	donor_loss	1.0000
19:42199833:C:CT	acceptor_gain	0.9900
19:42209694:ACCT:A	donor_loss	0.9900
19:42209696:CTACC:C	donor_loss	0.9900

AlphaMissense

2022 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:42199535:A:G	L295P	1.000
19:42199535:A:T	L295Q	1.000
19:42199577:G:A	T281I	1.000
19:42199582:G:C	F279L	1.000
19:42199582:G:T	F279L	1.000
19:42199583:A:C	F279C	1.000
19:42199583:A:G	F279S	1.000
19:42199584:A:G	F279L	1.000
19:42199595:A:G	L275P	1.000
19:42199623:A:C	Y266D	1.000
19:42199625:T:A	D265V	1.000
19:42199630:C:A	W263C	1.000
19:42199630:C:G	W263C	1.000
19:42199632:A:G	W263R	1.000
19:42199632:A:T	W263R	1.000
19:42199633:G:C	F262L	1.000
19:42199633:G:T	F262L	1.000
19:42199634:A:C	F262C	1.000
19:42199634:A:G	F262S	1.000
19:42199635:A:G	F262L	1.000
19:42199643:A:G	L259P	1.000
19:42199660:G:C	F253L	1.000
19:42199660:G:T	F253L	1.000
19:42199661:A:C	F253C	1.000
19:42199661:A:G	F253S	1.000
19:42199662:A:G	F253L	1.000
19:42199662:A:T	F253I	1.000
19:42199667:A:C	I251S	1.000
19:42199667:A:G	I251T	1.000
19:42199667:A:T	I251N	1.000

dbSNP variants (sampled 300 via entrez): RS1000562467 (19:42202193 T>A,C), RS1000596705 (19:42218776 T>C), RS1000664607 (19:42213220 T>A,C), RS1000684775 (19:42203010 G>T), RS1000758480 (19:42202648 C>G,T), RS1000814416 (19:42219062 T>C), RS1001110547 (19:42213645 G>A), RS1001124603 (19:42210330 T>A,C,G), RS1001176754 (19:42210043 G>A), RS1001335723 (19:42220236 C>T), RS1001711193 (19:42198884 T>C), RS1001714981 (19:42220468 A>G), RS1001770604 (19:42215747 C>A,T), RS1001833637 (19:42203671 A>T), RS1001864200 (19:42220193 T>A,C)

Disease associations

OMIM: gene MIM:617078 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): syndromic intellectual disability (MONDO:0000508)

Orphanet (1): Rare genetic syndromic intellectual disability (Orphanet:183763)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010143_27	Meat-related diet	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

64 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression	3
Tobacco Smoke Pollution	increases expression	3
Cyclosporine	increases expression	3
Vehicle Emissions	affects expression, increases reaction, decreases expression, increases abundance	2
Cadmium	increases abundance, increases expression	2
Estradiol	decreases expression, increases expression	2
Silver	increases expression	2
Valproic Acid	decreases expression, increases methylation	2
Cadmium Chloride	increases abundance, increases expression	2
Particulate Matter	affects expression, increases reaction, decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
sanguinarine	affects cotreatment, increases expression	1
bis(tri-n-butyltin)oxide	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	decreases expression	1
2-butenal	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	increases expression	1
zinc chromate	increases abundance, increases expression	1
beta-methylcholine	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
chloropicrin	increases expression	1
motexafin gadolinium	increases expression, affects reaction	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0X1	SEES3-1V human DEDD2, clone1	Embryonic stem cell	Male
CVCL_A0X2	SEES3-1V human DEDD2, clone2	Embryonic stem cell	Male
CVCL_A0X3	SEES3-1V human DEDD2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.