EDA

Summary

EDA (ectodysplasin A, HGNC:3157) is a protein-coding gene on chromosome Xq13.1, encoding Ectodysplasin-A (Q92838). Cytokine which is involved in epithelial-mesenchymal signaling during morphogenesis of ectodermal organs. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene.

Source: NCBI Gene 1896 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked hypohidrotic ectodermal dysplasia (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 714 total — 197 pathogenic, 90 likely-pathogenic
• Phenotypes (HPO): 82
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001399

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3157
Approved symbol	EDA
Name	ectodysplasin A
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	EDA1, XLHED, HED, XHED, ED1-A1, ED1-A2, EDA-A1, EDA-A2
Ensembl gene	ENSG00000158813
Ensembl biotype	protein_coding
OMIM	300451
Entrez	1896

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000338901, ENST00000374548, ENST00000374552, ENST00000374553, ENST00000502251, ENST00000503592, ENST00000510681, ENST00000524573, ENST00000525810, ENST00000527388, ENST00000530321, ENST00000533317, ENST00000616899

RefSeq mRNA: 5 — MANE Select: NM_001399 NM_001005609, NM_001005610, NM_001005612, NM_001005613, NM_001399

CCDS: CCDS14394, CCDS35318, CCDS35319, CCDS43966, CCDS55436

Canonical transcript exons

ENST00000374552 — 8 exons

Exon	Start	End
ENSE00001041165	70029504	70029538
ENSE00001041190	70030469	70030520
ENSE00001155510	70023218	70023241
ENSE00001164103	70027857	70028036
ENSE00001463796	70033398	70033528
ENSE00003759001	69957027	69957132
ENSE00003844683	69616113	69616704
ENSE00003848162	70035358	70039472

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 84.68.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2142 / max 17.6935, expressed in 565 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196608	1.0282	521
196609	0.1860	105

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tongue squamous epithelium	UBERON:0006919	84.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.69	gold quality
oocyte	CL:0000023	83.50	gold quality
adrenal tissue	UBERON:0018303	81.94	gold quality
type B pancreatic cell	CL:0000169	80.92	gold quality
olfactory bulb	UBERON:0002264	80.51	gold quality
right atrium auricular region	UBERON:0006631	79.60	gold quality
cardiac atrium	UBERON:0002081	79.10	gold quality
left adrenal gland	UBERON:0001234	78.25	gold quality
left adrenal gland cortex	UBERON:0035825	78.06	gold quality
secondary oocyte	CL:0000655	77.88	gold quality
right adrenal gland cortex	UBERON:0035827	77.86	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.72	gold quality
right adrenal gland	UBERON:0001233	77.70	gold quality
adrenal gland	UBERON:0002369	77.69	gold quality
adrenal cortex	UBERON:0001235	77.45	gold quality
apex of heart	UBERON:0002098	76.39	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.89	gold quality
hair follicle	UBERON:0002073	75.83	gold quality
choroid plexus epithelium	UBERON:0003911	75.62	silver quality
buccal mucosa cell	CL:0002336	75.27	gold quality
nasal cavity epithelium	UBERON:0005384	74.61	gold quality
heart	UBERON:0000948	74.03	gold quality
sural nerve	UBERON:0015488	73.95	gold quality
tendon of biceps brachii	UBERON:0008188	73.48	gold quality
left ventricle myocardium	UBERON:0006566	73.37	gold quality
heart left ventricle	UBERON:0002084	73.30	gold quality
ventricular zone	UBERON:0003053	73.14	gold quality
vena cava	UBERON:0004087	73.12	gold quality
cardiac ventricle	UBERON:0002082	73.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): LEF1

miRNA regulators (miRDB)

109 targeting EDA, 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-190A-3P	100.00	80.35	5520
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4671-3P	99.88	72.46	1045

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The structure of the EDA1 gene in a patient with anhidrotic ectodermal dysplasia (PMID:12673367)
• Identified ED1 mutations including one novel mutation in the 5’ splice site following exon 8 (IVS8+5delG) and another missense mutation (A959G; Y320C), which has been reported previously. (PMID:12682853)
• The ED1 gene was identified as a responsive gene for X-LINKED HYPOHIDROTIC ECTODERMAL DYSPLASIA. (PMID:12920369)
• identified ED1 mutations including three novel mutations by sequencing genomic DNAs from eight unrelated Japanese X-linked hypohidrotic ectodermal dysplasia families (PMID:12930312)
• point mutation (G1149A) in exon 8 changes codon 291 from glycine to arginine causing X-linked hypohidrotic ectodermal dysplasia (PMID:15663448)
• isoforms of EDA-A5 and A5’,activated NF-kappaB through receptors EDAR and XEDAR (PMID:16423472)
• EDA signaling has its biological significance in inducing development and morphogenesis of sweat glands and in maintaining physiological function of skin. (PMID:16752854)
• EDA signaling has a role in skin appendage development [review] (PMID:17102627)
• An amino acid substitution in ectodysplasin A is associated with X-linked dominant incisor hypodontia. (PMID:17256800)
• Report of a novel insertion mutation in EDA1 gene in a Pakistani family with x-linked hypohidrotic ectodermal dysplasia. (PMID:17478381)
• study reports the molecular analyses of four patients from India with hypohidrotic ectodermal dysplasia, three who harbour novel mutations, two in the EDA gene and one in the EDAR gene (PMID:17970812)
• Three novel missense mutations of the EDA gene have been identified. This provides evidence for an unequal homologous recombination between two LINE-1 elements as the molecular mechanism in the pathogensis of LXHED. (PMID:18076698)
• a novel deletion mutation is described in a Chinese family with X-linked hypohidrotic ectodermal dysplasia (PMID:18427821)
• results indicate that these novel missense mutations in EDA are associated with the isolated tooth agenesis and provide preliminary explanation for the abnormal clinical phenotype at a molecular structural level (PMID:18545687)
• In TGF-beta1 incubated CLPF mRNA amount of FN and isoforms ED-A and ED-B was slightly increased. IFN-gamma only decreased FN in CLPF, TNF significantly reduced FN-mRNA by 40%, FN ED-A mRNA by 25%, and ED-B mRNA by 50%. (PMID:18633626)
• congenital absence of maxillary and mandibular central incisors, lateral incisors and canines, with the high possibility of persistence of maxillary and mandibular first permanent molars as a pattern of tooth agenesis, suggests an EDA mutation (PMID:18657636)
• Screening of EDA1 gene in X-linked anhiderotic ectodermal dysplasia using DHPLC: identification of 14 novel mutations in Italian patients is reported. (PMID:18666859)
• Missense mutation in the EDA gene is associated with X-linked recessive isolated hypodontia (PMID:18688569)
• the c.952delG mutation of the EDA1 gene is likely to be the disease-causing mutation for XLHED in this family. (PMID:18702659)
• data confirm that mutations could cause both X-linked hipohydrotic ectodermal dysplasia and isolated hypodontia and provide evidence that EDA is a strong candidate gene for tooth genesis (PMID:18821982)
• Case Reports:Two novel mutations in the ED1 gene in Japanese families with X-linked hypohidrotic ectodermal dysplasia. (PMID:19127222)
• genetic defect could result in non-syndromic oligodontia in affected males (PMID:19278982)
• results expand the allelic series for mutations underlying hypohidrotic ectodermal dysplasia (PMID:19438931)
• We present a new mutation in the EDA gene which causes selective tooth agenesis and demonstrates the phenotype variation that can be encountered in the ectodermal dysplasia syndrome (HED) with the highest prevalence worldwide. (PMID:19504606)
• Recurrent mutations in functionally-related EDA and EDAR genes underlie X-linked isolated hypodontia and autosomal recessive hypohidrotic ectodermal dysplasia. (PMID:19551394)
• An in vitro functional analysis was performed of six selective tooth agenesis-causing EDA mutations (one novel and five known) that are located in the C-terminal tumor necrosis factor homology domain of the protein. (PMID:19623212)
• The collagen domain activates EDA1 by multimerization, whereas the proteoglycan-binding domain may restrict the distribution of endogeneous EDA1 in vivo. (PMID:19657145)
• EDA has been identified as a nonsyndromic tooth agenesis gene, X-linked. (PMID:19816326)
• Data show that 25 different mutations on EDA and EDAR genes were detected in HED patients. (PMID:20236127)
• analysis of Missense mutation of the EDA gene in a Jordanian family with X-linked hypohidrotic ectodermal dysplasia [case report] (PMID:20486090)
• A crucial role of the EDA-A2/ectodysplasin A2 (XEDAR) interaction is revealed in the p53-signaling pathway. (PMID:20501644)
• Direct sequencing of the EDA-A1 gene in affected individuals of the 3 families revealed the same missense mutation. Microsatellite marker analysis showed a shared haplotype among the affected members of both families, suggesting a common founder mutation. (PMID:20628232)
• EDA1 gene was the most common hypohidrotic/anhidrotic ectodermal dysplasia disease-causing gene (PMID:20979233)
• This study further confirms the differential effect of the mutations in EDA gene that define the pathogenic basis of X-linked recessive isolated hypodontia. (PMID:21091672)
• Systematic mapping of EDA mutations together with the analysis of objective clinical data may help to distinguish functionally crucial mutations from those allowing residual activity of the gene product. (PMID:21357618)
• there exists a correlation between the phenotypes and genotypes of XLHED and NSH subjects harboring EDA mutations (PMID:21457804)
• association in dental crowding in the Hong Kong Chinese population (PMID:21724072)
• The finding that EDAR370A attenuates hypohidrotic ectodermal dysplasia symptoms provides the first in vivo evidence that allele is a more potent signalling molecule than EDAR370V. (PMID:21916884)
• we report a novel mutation of the EDA gene identified in a Korean family with X-linked hypohidrotic ectodermal dysplasia. (PMID:22004506)
• Direct DNA sequencing of the whole coding region of EDA revealed a novel missense mutation, p.Leu354Pro in a patient affected with XLHED. (PMID:22008666)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	eda	ENSDARG00000074591
mus_musculus	Eda	ENSMUSG00000059327
rattus_norvegicus	Eda	ENSRNOG00000032208

Paralogs (37): COL9A2 (ENSG00000049089), COL23A1 (ENSG00000050767), COL11A1 (ENSG00000060718), COL17A1 (ENSG00000065618), COL5A3 (ENSG00000080573), COL4A4 (ENSG00000081052), COL16A1 (ENSG00000084636), COL9A3 (ENSG00000092758), COL20A1 (ENSG00000101203), COL1A1 (ENSG00000108821), COL9A1 (ENSG00000112280), COL7A1 (ENSG00000114270), COL21A1 (ENSG00000124749), COL5A1 (ENSG00000130635), COL4A2 (ENSG00000134871), COL2A1 (ENSG00000139219), COL6A1 (ENSG00000142156), COL6A2 (ENSG00000142173), COL26A1 (ENSG00000160963), COL1A2 (ENSG00000164692), COL3A1 (ENSG00000168542), COL4A3 (ENSG00000169031), COL22A1 (ENSG00000169436), COL24A1 (ENSG00000171502), COL18A1 (ENSG00000182871), EMID1 (ENSG00000186998), COL4A1 (ENSG00000187498), COL4A5 (ENSG00000188153), COL25A1 (ENSG00000188517), COL27A1 (ENSG00000196739), COL13A1 (ENSG00000197467), COL4A6 (ENSG00000197565), COL11A2 (ENSG00000204248), COL5A2 (ENSG00000204262), COL15A1 (ENSG00000204291), COLQ (ENSG00000206561), COL28A1 (ENSG00000215018)

Protein

Protein identifiers

Ectodysplasin-A — Q92838 (reviewed: Q92838)

Alternative names: Ectodermal dysplasia protein

All UniProt accessions (4): A0A0C4DGX3, A0A0U5J797, D6RA95, Q92838

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine which is involved in epithelial-mesenchymal signaling during morphogenesis of ectodermal organs. Functions as a ligand activating the DEATH-domain containing receptors EDAR and EDA2R. May also play a role in cell adhesion. Binds only to the receptor EDAR, while isoform 3 binds exclusively to the receptor EDA2R. Binds only to the receptor EDA2R.

Subunit / interactions. Homotrimer. The homotrimers may then dimerize and form higher-order oligomers.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Not abundant; expressed in specific cell types of ectodermal (but not mesodermal) origin of keratinocytes, hair follicles, sweat glands. Also in adult heart, liver, muscle, pancreas, prostate, fetal liver, uterus, small intestine and umbilical cord.

Post-translational modifications. N-glycosylated. Processing by furin produces a secreted form.

Disease relevance. Ectodermal dysplasia 1, hypohidrotic, X-linked (XHED) [MIM:305100] A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Characterized by sparse hair (atrichosis or hypotrichosis), abnormal or missing teeth and the inability to sweat due to the absence of sweat glands. It is the most common form of over 150 clinically distinct ectodermal dysplasias. The disease is caused by variants affecting the gene represented in this entry. Tooth agenesis, selective, X-linked, 1 (STHAGX1) [MIM:313500] A form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the tumor necrosis factor family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q92838-1	1, A1, II, EDA1	yes
Q92838-2	2, I
Q92838-3	3, A2, EDA2
Q92838-5	4, C
Q92838-6	5, D
Q92838-7	6, E
Q92838-8	7, F
Q92838-9	8

RefSeq proteins (5): NP_001005609, NP_001005610, NP_001005612, NP_001005613, NP_001390* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006052	TNF_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR051748	TNF_Ligand_Superfamily	Family

Pfam: PF00229

UniProt features (141 total): sequence variant 93, strand 15, splice variant 10, compositionally biased region 4, turn 3, chain 2, helix 2, glycosylation site 2, topological domain 2, domain 2, region of interest 2, mutagenesis site 1, site 1, disulfide bond 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1RJ8	X-RAY DIFFRACTION	2.23
1RJ7	X-RAY DIFFRACTION	2.3
7X9G	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92838-F1	70.59	0.38

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 159–160 (cleavage; by furin)

Disulfide bonds (1): 332–346

Glycosylation sites (2): 313, 372

Mutagenesis-validated functional residues (1):

Position	Phenotype
159	abolishes proteolytic processing.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5669034	TNFs bind their physiological receptors

MSigDB gene sets: 359 (showing top): RRAGTTGT_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, CCAWYNNGAAR_UNKNOWN, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, GOBP_SALIVARY_GLAND_DEVELOPMENT, NKX25_02, GOCC_COLLAGEN_TRIMER, GCANCTGNY_MYOD_Q6, MODULE_45, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY

GO Biological Process (20): immune response (GO:0006955), cell-matrix adhesion (GO:0007160), gene expression (GO:0010467), positive regulation of gene expression (GO:0010628), cytokine-mediated signaling pathway (GO:0019221), cell differentiation (GO:0030154), odontogenesis of dentin-containing tooth (GO:0042475), odontogenesis (GO:0042476), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), pigmentation (GO:0043473), canonical Wnt signaling pathway (GO:0060070), salivary gland cavitation (GO:0060662), hair follicle placode formation (GO:0060789), trachea gland development (GO:0061153), positive regulation of canonical Wnt signaling pathway (GO:0090263), regulation of non-canonical NF-kappaB signal transduction (GO:1901222), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), hair follicle development (GO:0001942), cell surface receptor signaling pathway (GO:0007166), skin development (GO:0043588)

GO Molecular Function (6): signaling receptor binding (GO:0005102), death receptor binding (GO:0005123), cytokine activity (GO:0005125), tumor necrosis factor receptor binding (GO:0005164), death receptor agonist activity (GO:0038177), protein binding (GO:0005515)

GO Cellular Component (9): collagen trimer (GO:0005581), obsolete extracellular space (GO:0005615), endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), apical part of cell (GO:0045177), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of intracellular signal transduction	2
non-canonical NF-kappaB signal transduction	2
tumor necrosis factor receptor superfamily binding	2
receptor ligand activity	2
intracellular membraneless organelle	2
immune system process	1
response to stimulus	1
cell-substrate adhesion	1
macromolecule biosynthetic process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
cellular developmental process	1
odontogenesis	1
animal organ morphogenesis	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
biological_process	1
Wnt signaling pathway	1
salivary gland morphogenesis	1
tube lumen cavitation	1
hair follicle development	1
ectodermal placode formation	1
gland development	1
trachea submucosa development	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
regulation of intracellular signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
signal transduction	1
animal organ development	1
protein binding	1
death receptor activity	1

Protein interactions and networks

STRING

456 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EDA	EDAR	Q9UNE0	999
EDA	EDA2R	Q9HAV5	967
EDA	WNT10A	Q9GZT5	922
EDA	EDARADD	Q8WWZ3	922
EDA	PAX9	P55771	780
EDA	TNF	P01375	698
EDA	FN1	P02751	621
EDA	MSX1	P28360	598
EDA	SOSTDC1	Q6X4U4	591
EDA	LTBP3	Q9NS15	582
EDA	LTBP2	Q14767	567
EDA	UBR5	O95071	525
EDA	DKK4	Q9UBT3	523
EDA	TNFSF12	O43508	500
EDA	TNFSF15	O95150	491

IntAct

141 interactions, top by confidence:

A	B	Type	Score
PLN	EDA	psi-mi:“MI:0915”(physical association)	0.890
EDA	PLN	psi-mi:“MI:0915”(physical association)	0.890
EDA	NIPAL3	psi-mi:“MI:0915”(physical association)	0.830
NIPAL3	EDA	psi-mi:“MI:0915”(physical association)	0.830
MAL	EDA	psi-mi:“MI:0915”(physical association)	0.780
EDA	EMP3	psi-mi:“MI:0915”(physical association)	0.780
SEC22A	EDA	psi-mi:“MI:0915”(physical association)	0.780
EDA	MAL	psi-mi:“MI:0915”(physical association)	0.780
EMP3	EDA	psi-mi:“MI:0915”(physical association)	0.780
EDA	SEC22A	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (195): EDA (Two-hybrid), EDA (Two-hybrid), EMP3 (Two-hybrid), MAL (Two-hybrid), PLN (Two-hybrid), DOLK (Two-hybrid), LEPROTL1 (Two-hybrid), SEC22A (Two-hybrid), GIMAP5 (Two-hybrid), NIPAL3 (Two-hybrid), OSTC (Two-hybrid), OSTCP1 (Two-hybrid), EDA (Affinity Capture-MS), EDA (Affinity Capture-MS), EDA (Affinity Capture-MS)

ESM2 similar proteins: A0MTF4, A4Q9F4, M3X9S6, O15520, O35565, O43189, O43320, O54693, O54769, O73754, O95750, P05524, P08620, P11487, P12034, P15656, P31371, P36364, P36386, P48801, P48802, P48803, P48804, P48807, P54130, P70492, P97401, P98172, Q20FD0, Q2HXK8, Q3ZFI5, Q5RF67, Q5T6S3, Q5XI70, Q91875, Q92765, Q92838, Q95117, Q95L12, Q96GD3

Diamond homologs: O54693, Q92838, Q9BEG5, O75888, Q9D777, Q9WU72, Q9Y275

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EDA	up-regulates	EDAR	binding
EDA	up-regulates	EDA2R	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transmembrane transport	5	17.6×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	197
Likely pathogenic	90
Uncertain significance	117
Likely benign	173
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068988	NM_001399.5(EDA):c.486_487insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGGAGATCGAGACCATCCTGGCTAACAAGGTGAANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAGAAGCAAAAGC (p.Asn163delinsGlyArgAlaArgTrpLeuThrProValIleProAlaLeuTrpGluAlaGluAlaGlyGlySerTer)	Pathogenic
1070893	NM_001399.5(EDA):c.1A>G (p.Met1Val)	Pathogenic
1070894	NM_001399.5(EDA):c.643G>T (p.Gly215Ter)	Pathogenic
1070895	NM_001399.5(EDA):c.632C>G (p.Thr211Arg)	Pathogenic
1070896	NM_001399.5(EDA):c.801A>G (p.Ser267=)	Pathogenic
1071445	NM_001399.5(EDA):c.497del (p.Ala166fs)	Pathogenic
1071552	NM_001399.5(EDA):c.213del (p.Glu71fs)	Pathogenic
1071684	NM_001399.5(EDA):c.614_699del (p.Ile205fs)	Pathogenic
1071925	NM_001399.5(EDA):c.441dup (p.Glu148Ter)	Pathogenic
1072490	NM_001399.5(EDA):c.576_592del (p.Pro193fs)	Pathogenic
1072863	NM_001399.5(EDA):c.1009G>T (p.Glu337Ter)	Pathogenic
1076054	NM_001399.5(EDA):c.585_697del (p.Pro196fs)	Pathogenic
1076088	NM_001399.5(EDA):c.223G>T (p.Glu75Ter)	Pathogenic
1076565	NM_001399.5(EDA):c.216_220del (p.Gly73fs)	Pathogenic
11033	NM_001399.5(EDA):c.67C>T (p.Gln23Ter)	Pathogenic
11035	NM_001399.5(EDA):c.463C>T (p.Arg155Cys)	Pathogenic
11037	NM_001399.5(EDA):c.467G>A (p.Arg156His)	Pathogenic
11039	NM_001399.5(EDA):c.671G>C (p.Gly224Ala)	Pathogenic
11040	NM_001399.5(EDA):c.1045G>A (p.Ala349Thr)	Pathogenic
11041	NM_001399.5(EDA):c.183C>G (p.Tyr61Ter)	Pathogenic
11042	EDA, 36-BP DEL, EX5	Pathogenic
11043	EDA, 1-BP DEL, EX6	Pathogenic
11044	NM_001399.5(EDA):c.193C>G (p.Arg65Gly)	Pathogenic
11045	NM_001399.5(EDA):c.1072C>G (p.Gln358Glu)	Pathogenic
11046	NM_001399.5(EDA):c.573_574insT (p.Gly192fs)	Pathogenic
11047	NM_001399.5(EDA):c.912_913dup (p.Ser305fs)	Pathogenic
11048	NM_001399.5(EDA):c.1013C>T (p.Thr338Met)	Pathogenic
1185006	NM_001399.5(EDA):c.602G>A (p.Gly201Glu)	Pathogenic
1185007	NM_001399.5(EDA):c.628G>A (p.Gly210Arg)	Pathogenic
1185008	NM_001399.5(EDA):c.707-2A>T	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2513 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:70030485:T:C	L253P	1.000
X:70030490:G:C	G255R	1.000
X:70030491:G:A	G255D	1.000
X:70033416:T:A	L271H	1.000
X:70033416:T:C	L271P	1.000
X:70033424:T:A	W274R	1.000
X:70033424:T:C	W274R	1.000
X:70033425:G:C	W274S	1.000
X:70033426:G:C	W274C	1.000
X:70033426:G:T	W274C	1.000
X:70033454:T:C	F284L	1.000
X:70033455:T:C	F284S	1.000
X:70033456:T:A	F284L	1.000
X:70033456:T:G	F284L	1.000
X:70033476:G:A	G291E	1.000
X:70033482:T:C	L293P	1.000
X:70033499:G:C	G299R	1.000
X:70033500:G:T	G299V	1.000
X:70033505:T:G	Y301D	1.000
X:70033514:T:G	Y304D	1.000
X:70033517:A:C	S305R	1.000
X:70033519:T:A	S305R	1.000
X:70033519:T:G	S305R	1.000
X:70033521:A:C	Q306P	1.000
X:70035386:C:A	A318D	1.000
X:70035422:T:C	L330P	1.000
X:70035427:T:A	C332S	1.000
X:70035427:T:C	C332R	1.000
X:70035428:G:A	C332Y	1.000
X:70035428:G:C	C332S	1.000

dbSNP variants (sampled 300 via entrez): RS1000000029 (X:69951405 A>G), RS1000009570 (X:69716284 A>G,T), RS1000012977 (X:69712584 G>A,T), RS1000023935 (X:69763328 C>G), RS1000040661 (X:69919375 A>G), RS1000051108 (X:69699869 C>T), RS1000070164 (X:69692205 A>G), RS1000086695 (X:69816477 A>G), RS1000092398 (X:69775320 A>C), RS1000122443 (X:69663571 G>A), RS1000129599 (X:69692731 G>A), RS1000142982 (X:69952301 G>A), RS1000159277 (X:70031284 G>A,T), RS1000161495 (X:70002100 T>A), RS1000167193 (X:69659197 C>G)

Disease associations

OMIM: gene MIM:300451 | disease phenotypes: MIM:305100, MIM:313500, MIM:613091, MIM:106600, MIM:602639

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked hypohidrotic ectodermal dysplasia	Definitive	X-linked
tooth agenesis, selective, X-linked, 1	Definitive	X-linked
tooth agenesis	Supportive	Autosomal dominant

Mondo (6): X-linked hypohidrotic ectodermal dysplasia (MONDO:0010585), tooth agenesis, selective, X-linked, 1 (MONDO:0010741), ectodermal dysplasia syndrome (MONDO:0019287), asphyxiating thoracic dystrophy 3 (MONDO:0013127), tooth agenesis (MONDO:0005486), tooth agenesis, selective, 2 (MONDO:0011265)

Orphanet (9): X-linked hypohidrotic ectodermal dysplasia (Orphanet:181), Hypohidrotic ectodermal dysplasia (Orphanet:238468), Oligodontia (Orphanet:99798), Ectodermal dysplasia syndrome (Orphanet:79373), Jeune syndrome (Orphanet:474), Short rib-polydactyly syndrome, Majewski type (Orphanet:93269), Short rib-polydactyly syndrome, Saldino-Noonan type (Orphanet:93270), Short rib-polydactyly syndrome, Verma-Naumoff type (Orphanet:93271), NON RARE IN EUROPE: Hypodontia (Orphanet:2227)

HPO phenotypes

82 total (30 of 82 shown, HPO-id order):

HPO	Term
HP:0000202	Orofacial cleft
HP:0000232	Everted lower lip vermilion
HP:0000327	Hypoplasia of the maxilla
HP:0000331	Short chin
HP:0000336	Prominent supraorbital ridges
HP:0000430	Underdeveloped nasal alae
HP:0000457	Depressed nasal ridge
HP:0000561	Absent eyelashes
HP:0000607	Periorbital wrinkles
HP:0000653	Sparse eyelashes
HP:0000668	Hypodontia
HP:0000674	Anodontia
HP:0000677	Oligodontia
HP:0000679	Taurodontia
HP:0000684	Delayed eruption of teeth
HP:0000685	Hypoplasia of teeth
HP:0000687	Widely spaced teeth
HP:0000689	Dental malocclusion
HP:0000690	Agenesis of maxillary lateral incisor
HP:0000691	Microdontia
HP:0000696	Delayed eruption of permanent teeth
HP:0000698	Conical tooth
HP:0000822	Hypertension
HP:0000830	Anterior hypopituitarism
HP:0000958	Dry skin
HP:0000963	Thin skin
HP:0000964	Eczematoid dermatitis
HP:0000966	Hypohidrosis
HP:0000970	Anhidrosis
HP:0000977	Soft skin

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000609_3	Primary tooth development (time to first tooth eruption)	6.000000e-11
GCST000610_4	Primary tooth development (number of teeth)	5.000000e-11
GCST002030_13	Primary tooth development (time to first tooth eruption)	3.000000e-22
GCST002031_11	Primary tooth development (number of teeth)	7.000000e-19
GCST003996_6	Monobrow	9.000000e-36
GCST005391_2	Tooth agenesis (maxillary lateral incisors)	5.000000e-12
GCST007020_415	Male-pattern baldness	1.000000e-15
GCST009391_1573	Metabolite levels	8.000000e-06
GCST009391_1732	Metabolite levels	7.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007906	synophrys measurement
EFO:0007825	balding measurement
EFO:0010516	orotic acid measurement
EFO:0010375	phosphatidylcholine 34:1 measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004476	Ectodermal Dysplasia	C16.131.077.350; C16.131.831.350; C16.320.850.250; C17.800.804.350; C17.800.827.250
C537602	Short rib-polydactyly syndrome, Verma-Naumoff type (supp.)
C566513	Tooth Agenesis, Selective, 2 (supp.)
C567060	Tooth Agenesis, Selective, X-Linked, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	5
bisphenol A	increases expression, increases methylation, affects cotreatment, decreases expression	3
Benzo(a)pyrene	decreases expression, increases methylation, affects methylation	3
fluorene-9-bisphenol	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
PF 3758309	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Bucladesine	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Endosulfan	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Formaldehyde	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Nickel	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Vitamin E	decreases expression	1
Zinc	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Medroxyprogesterone Acetate	affects cotreatment, increases expression	1

Cellosaurus cell lines

6 cell lines: 3 transformed cell line, 1 cancer cell line, 1 finite cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D8KM	Ubigene HCT 116 EDA KO	Cancer cell line	Male
CVCL_D9DX	Ubigene HEK293 EDA KO	Transformed cell line	Female
CVCL_RT81	GM26595	Transformed cell line	Male
CVCL_RT82	GM26596	Finite cell line	Male
CVCL_RT83	GM26597	Transformed cell line	Female
CVCL_UL61	WAe001-A-22	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01775462	PHASE2	COMPLETED	Phase 2 Study to Evaluate Safety, Pharmacokinetics, Immunogenicity and Pharmacodynamics/Efficacy of EDI200 in Male Infants With X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)
NCT04980638	PHASE2	RECRUITING	Intraamniotic Administrations of ER004 to Male Subjects With X-linked Hypohidrotic Ectodermal Dysplasia
NCT01564225	PHASE1	COMPLETED	A Phase 1, Open-label, Multicenter, Safety and Pharmacokinetic Study of EDI200
NCT01135888	Not specified	COMPLETED	Short Term Effects and Risks of Physical Exercise in Subjects With Hypohidrotic Ectodermal Dysplasia
NCT01308333	Not specified	COMPLETED	Investigation of Chronic Inflammatory Processes in Male Individuals With Hypohidrotic Ectodermal Dysplasia
NCT01342133	Not specified	COMPLETED	Sweat Duct Imaging in Mother/Newborn Dyads
NCT01398397	Not specified	COMPLETED	Medical Record Review of Hypohidrotic Ectodermal Dysplasia Clinical Phenotype
NCT01398813	Not specified	COMPLETED	X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) Carrier Outlook Toward Reproduction Survey
NCT01629927	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia (ECP-012)
NCT01629940	Not specified	COMPLETED	Phenotypic and Genetic Properties in Males at Risk for X-linked Hypohidrotic Ectodermal Dysplasia: Evaluation of an Early Diagnosis Technology and Tests to Assess Nutritional Status
NCT01871714	Not specified	COMPLETED	Phenotypic Properties in Individuals Affected With XLHED
NCT01992289	Not specified	UNKNOWN	Extension Study of XLHED-Affected Male Subjects Treated With EDI200 in Protocol ECP-002
NCT02099552	Not specified	COMPLETED	Natural History and Outcomes in X-Linked Hypohidrotic Ectodermal Dysplasia
NCT07096206	Not specified	ACTIVE_NOT_RECRUITING	Characteristics and Impacts of X-linked Hypohidrotic Ectodermal Dysplasia (XLHED) in Boys: An Observational International Study
NCT01470235	Not specified	UNKNOWN	Hypodontia and Ovarian Cancer
NCT03445026	Not specified	UNKNOWN	Frequency of Hypodontia After Chemotherapy in Childhood Cancer Survivors Study
NCT05771246	Not specified	COMPLETED	Craniofacial Morphology And Sella Turcica Bridging Associated With Third Molar Agenesis.
NCT00001211	Not specified	COMPLETED	Clinical Study of Oral Endosseous Titanium Implants in Edentulous Subjects
NCT00266513	Not specified	TERMINATED	Studies of Disorders in Antibody Production and Related Primary Immunodeficiency States
NCT01108770	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia
NCT02896387	Not specified	TERMINATED	Ability of a Molecule (Prima) to Restore Physiological Differentiation in Epithelium Expressing Gene p63
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07468019	Not specified	RECRUITING	Organization’s Unique Protocol ID