DEFA4

Summary

DEFA4 (defensin alpha 4, HGNC:2763) is a protein-coding gene on chromosome 8p23.1, encoding Defensin alpha 4 (P12838). Host-defense peptide that has antimicrobial activity against Gram-negative bacteria, and to a lesser extent also against Gram-positive bacteria and fungi.

Defensins are a family of antimicrobial and cytotoxic peptides thought to be involved in host defense. They are abundant in the granules of neutrophils and also found in the epithelia of mucosal surfaces such as those of the intestine, respiratory tract, urinary tract, and vagina. Members of the defensin family are highly similar in protein sequence and distinguished by a conserved cysteine motif. Several alpha defensin genes are clustered on chromosome 8. This gene differs from other genes of this family by an extra 83-base segment that is apparently the result of a recent duplication within the coding region. The protein encoded by this gene, defensin, alpha 4, is found in the neutrophils; it exhibits corticostatic activity and inhibits corticotropin stimulated corticosterone production.

Source: NCBI Gene 1669 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_001925

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2763
Approved symbol	DEFA4
Name	defensin alpha 4
Location	8p23.1
Locus type	gene with protein product
Status	Approved
Aliases	HP-4
Ensembl gene	ENSG00000164821
Ensembl biotype	protein_coding
OMIM	601157
Entrez	1669

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000297435

RefSeq mRNA: 1 — MANE Select: NM_001925 NM_001925

CCDS: CCDS5961

Canonical transcript exons

ENST00000297435 — 3 exons

Exon	Start	End
ENSE00001087786	6935820	6936141
ENSE00001087788	6936728	6936911
ENSE00001866227	6938226	6938306

Expression profiles

Bgee: expression breadth ubiquitous, 110 present calls, max score 99.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 7.7562 / max 6020.2852, expressed in 63 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91716	7.7562	63

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone element	UBERON:0001474	99.54	gold quality
bone marrow	UBERON:0002371	99.54	gold quality
bone marrow cell	CL:0002092	99.17	gold quality
monocyte	CL:0000576	94.39	gold quality
leukocyte	CL:0000738	92.83	gold quality
blood	UBERON:0000178	87.52	gold quality
granulocyte	CL:0000094	85.31	gold quality
spleen	UBERON:0002106	81.38	gold quality
right lung	UBERON:0002167	78.36	gold quality
upper lobe of left lung	UBERON:0008952	65.08	gold quality
placenta	UBERON:0001987	63.00	gold quality
right lobe of liver	UBERON:0001114	59.53	gold quality
lung	UBERON:0002048	59.06	gold quality
lymph node	UBERON:0000029	56.78	gold quality
liver	UBERON:0002107	51.89	gold quality
descending thoracic aorta	UBERON:0002345	47.94	gold quality
vermiform appendix	UBERON:0001154	46.94	gold quality
heart left ventricle	UBERON:0002084	44.13	gold quality
omental fat pad	UBERON:0010414	44.07	gold quality
hindlimb stylopod muscle	UBERON:0004252	43.86	gold quality
apex of heart	UBERON:0002098	42.62	silver quality
lower esophagus mucosa	UBERON:0035834	41.56	silver quality
heart	UBERON:0000948	41.45	gold quality
duodenum	UBERON:0002114	40.96	gold quality
adipose tissue	UBERON:0001013	40.79	gold quality
right atrium auricular region	UBERON:0006631	40.64	gold quality
gastrocnemius	UBERON:0001388	40.53	gold quality
putamen	UBERON:0001874	39.77	gold quality
left lobe of thyroid gland	UBERON:0001120	39.69	gold quality
adenohypophysis	UBERON:0002196	39.50	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	2024.36
E-ANND-3	no	0.56

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting DEFA4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-6816-3P	95.05	66.08	459

Literature-anchored findings (GeneRIF, showing 8)

• Crystal structure of HNP-4. (PMID:17088326)
• DEFA4 was upregulated in IPF patients with acute exacerbation (PMID:19363140)
• The combination of an increased expression of the antimicrobial peptide DEFA-4, the oncogene S100-A7, epidermal growth factor, and tenascin-c, and a decreased Doc-1 expression in oral leukoplakia might characterize its potency of malignant transformation. (PMID:20727496)
• DEFA1-3 and DEFA4 mRNA level in peripheral blood cells can be used to identify chronic myeloid leukaemia patients who are at risk of being imatinib-resistant, before initiation of the therapy. (PMID:21734341)
• Results indicate that the gene expression of DEFA 1/3 and 4 was significantly increased in all tumours - except for a significant decrease of DEFA 4 gene expression in pleomorphic adenomas. (PMID:23050799)
• DEFA4 displays antimicrobial activity against E. coli, S. faecalis, and C. albicans. (PMID:2500436)
• Three AMP genes, histatin 3 (HTN3), alpha-defensin 4 (DEFA4) and lysozyme C (LYZ), presented different expression levels in periodontitis patients compared with healthy subjects. The relative expression level of DEFA4 appeared to be a protective factor against periodontitis. (PMID:29446150)
• findings unveil the molecular determinants of HNP4 function, completing the atlas of structure and function relationships for all human neutrophil alpha-defensins. (PMID:30658057)

Cross-species orthologs

40 orthologs

Organism	Symbol	Gene ID
mus_musculus	Defa39	ENSMUSG00000058618
mus_musculus	Defa26	ENSMUSG00000060070
mus_musculus	Defa17	ENSMUSG00000060208
mus_musculus	Defa35	ENSMUSG00000061845
mus_musculus	Defa38	ENSMUSG00000061958
mus_musculus	Defa34	ENSMUSG00000063206
mus_musculus	Defa24	ENSMUSG00000064213
mus_musculus	Defa37	ENSMUSG00000065956
mus_musculus	Defa28	ENSMUSG00000074434
mus_musculus	Defa29	ENSMUSG00000074437
mus_musculus	Defa5	ENSMUSG00000074439
mus_musculus	Defa3	ENSMUSG00000074440
mus_musculus	Defa40	ENSMUSG00000074441
mus_musculus	Defa31	ENSMUSG00000074442
mus_musculus	Defa22	ENSMUSG00000074443
mus_musculus	Defa30	ENSMUSG00000074444
mus_musculus	Defa23	ENSMUSG00000074446
mus_musculus	Defa21	ENSMUSG00000074447
mus_musculus	Defa43	ENSMUSG00000079113
mus_musculus	Defa42	ENSMUSG00000079114
mus_musculus	Defa41	ENSMUSG00000079116
mus_musculus	AY761185	ENSMUSG00000079120
mus_musculus	Defa33	ENSMUSG00000094362
mus_musculus	Defa36	ENSMUSG00000094662
mus_musculus	Defa25	ENSMUSG00000094687
mus_musculus	Defa32	ENSMUSG00000094818
mus_musculus	Defa20	ENSMUSG00000095066
mus_musculus	Defa2	ENSMUSG00000096295
rattus_norvegicus	Np4	ENSRNOG00000028707
rattus_norvegicus	Defal1	ENSRNOG00000029462
rattus_norvegicus	Defa5	ENSRNOG00000030093
rattus_norvegicus	Defa24	ENSRNOG00000030524
rattus_norvegicus	Defa3	ENSRNOG00000038133
rattus_norvegicus	RatNP-3b	ENSRNOG00000038135
rattus_norvegicus	Defa31	ENSRNOG00000061751
rattus_norvegicus	Defa9	ENSRNOG00000068468
rattus_norvegicus	Np4	ENSRNOG00000069755
rattus_norvegicus		ENSRNOG00000078458
rattus_norvegicus	Defa8	ENSRNOG00000081022
rattus_norvegicus	Defa9	ENSRNOG00000091367

Paralogs (5): DEFA5 (ENSG00000164816), DEFA6 (ENSG00000164822), DEFA1 (ENSG00000206047), DEFA3 (ENSG00000239839), DEFA1B (ENSG00000240247)

Protein

Protein identifiers

Defensin alpha 4 — P12838 (reviewed: P12838)

Alternative names: Corticostatin HP-4, HNP-4, Neutrophil defensin 4

All UniProt accessions (1): P12838

UniProt curated annotations — full annotation on UniProt →

Function. Host-defense peptide that has antimicrobial activity against Gram-negative bacteria, and to a lesser extent also against Gram-positive bacteria and fungi. Exhibits antimicrobial activity against Gram-negative E.coli and E.aerogenes and Gram-positive S.faecalis, S.aureus and B.cereus and the yeast C.albicans (in vitro). Interacts with pathogenic surface proteins and toxins, such as HIV-1 surface protein gp120 and B.anthracis anthrax lethal factor lef. Protects blood cells against infection with HIV-1 (in vitro). Inhibits enzymatic activity of B.anthracis lef/anthrax lethal factor (in vitro). Inhibits corticotropin (ACTH)-stimulated corticosterone production (in vitro).

Subunit / interactions. Homodimer; homodimerization seems to be required for killing S.aureus, but not E.coli. Interacts with CD4. Interacts with HIV-1 surface protein gp120; homodimerization is required for the interaction. Interacts with Bacillus anthracis lef; homodimerization is required for the interaction.

Subcellular location. Secreted. Cytoplasmic vesicle. Secretory vesicle.

Tissue specificity. Expressed in neutrophils (at protein level). Expressed in bone marrow.

Post-translational modifications. The three-dimensional structure formed by the three intramolecular disulfide bridges is indispensable for effective bacterial killing.

Similarity. Belongs to the alpha-defensin family.

RefSeq proteins (1): NP_001916* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002366	Alpha-defensin_N	Domain
IPR006080	Beta/alpha-defensin_C	Domain
IPR006081	Alpha-defensin_C	Domain
IPR016327	Alpha-defensin	Family

Pfam: PF00323, PF00879

UniProt features (27 total): mutagenesis site 14, strand 3, disulfide bond 3, sequence variant 3, propeptide 2, signal peptide 1, peptide 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1ZMM	X-RAY DIFFRACTION	1.6
6DMM	X-RAY DIFFRACTION	1.67
6DMQ	X-RAY DIFFRACTION	1.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12838-F1	69.45	0.32

Functional residue map

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

Disulfide bonds (3): 65–93, 67–82, 72–92

Mutagenesis-validated functional residues (14):

Position	Phenotype
65	impairs bactericidal activity against e.coli and s.aureus; when associated with ala-67, ala-72, ala-82, ala-92 and ala-9
67	impairs bactericidal activity against e.coli and s.aureus; when associated with ala-65, ala-72, ala-82, ala-92 and ala-9
69	slight decrease in antibacterial activity against e.coli.
71	decreased antibacterial activity against s.aureus.
72	impairs bactericidal activity against e.coli and s.aureus; when associated with ala-65, ala-67, ala-82, ala-92 and ala-9
73	decreased antibacterial activity against e.coli. weakens interaction with b.anthracis lef and with hiv-1 gp120.
74	decreased antibacterial activity against e.coli. weakens interaction with b.anthracis lef and with hiv-1 gp120.
78	decreased antibacterial activity against e.coli and s.aureus. weakens interaction with b.anthracis lef and with hiv-1 gp
82	impairs bactericidal activity against e.coli and s.aureus; when associated with ala-65, ala-67, ala-72, ala-92 and ala-9
89	impaired homodimerization. decreased antibacterial activity against s.aureus. disrupts interaction with b.anthracis lef
91	slight decrease in antibacterial activity against e.coli and s.aureus.
92	impairs bactericidal activity against e.coli and s.aureus; when associated with ala-65, ala-67, ala-72, ala-82 and ala-9
93	impairs bactericidal activity against e.coli and s.aureus; when associated with ala-65, ala-67, ala-72, ala-82 and ala-9
95	slight decrease in antibacterial activity against e.coli and s.aureus.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1461973	Defensins
R-HSA-1462054	Alpha-defensins
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 90 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_CELL_CHEMOTAXIS, GOCC_SECRETORY_GRANULE, CHEOK_RESPONSE_TO_HD_MTX_UP, GOBP_LEUKOCYTE_CHEMOTAXIS, GOBP_TAXIS, GOBP_LEUKOCYTE_MIGRATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, RHEIN_ALL_GLUCOCORTICOID_THERAPY_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_HUMORAL_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_GRAM_NEGATIVE_BACTERIUM, GOBP_T_CELL_MIGRATION, GOBP_LYMPHOCYTE_CHEMOTAXIS

GO Biological Process (12): antimicrobial humoral response (GO:0019730), antibacterial humoral response (GO:0019731), antifungal humoral response (GO:0019732), killing of cells of another organism (GO:0031640), innate immune response (GO:0045087), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), defense response to fungus (GO:0050832), disruption of plasma membrane integrity in another organism (GO:0051673), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), defense response (GO:0006952), defense response to bacterium (GO:0042742)

GO Molecular Function (2): protein homodimerization activity (GO:0042803), pore-forming activity (GO:0140911)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi lumen (GO:0005796), transport vesicle (GO:0030133), specific granule lumen (GO:0035580), azurophil granule (GO:0042582), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Antimicrobial peptides	1
Defensins	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
antimicrobial humoral response	3
defense response to bacterium	3
defense response to symbiont	2
defense response	2
humoral immune response	1
defense response to fungus	1
cell killing	1
disruption of cell in another organism	1
immune response	1
response to fungus	1
disruption of cellular anatomical structure in another organism	1
response to stress	1
response to bacterium	1
identical protein binding	1
protein dimerization activity	1
molecular_function	1
cellular anatomical structure	1
Golgi apparatus	1
intracellular organelle lumen	1
endomembrane system	1
cytoplasmic vesicle	1
secretory granule lumen	1
specific granule	1
primary lysosome	1
secretory granule	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

490 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DEFA4	DEFB1	P60022	830
DEFA4	DEFB4A	O15263	731
DEFA4	CTSG	P08311	680
DEFA4	PGLYRP1	O75594	654
DEFA4	MMP8	P22894	650
DEFA4	LCN2	P30150	638
DEFA4	MMP7	P09237	635
DEFA4	ART1	P52961	549
DEFA4	OLFM4	Q6UX06	541
DEFA4	CEACAM8	P31997	508
DEFA4	LTF	P02788	507
DEFA4	ELANE	P08246	507
DEFA4	RETN	Q9HD89	505
DEFA4	CEACAM6	P40199	478
DEFA4	TCN1	P20061	470

IntAct

2 interactions, top by confidence:

A	B	Type	Score
P/V/C	KPNA3	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A1W2PP97, A6NLX4, A6QNY1, P0DJK0, P12838, P13207, P22389, P22749, P23943, P29473, P29474, P55056, P70313, P79209, P97270, P98162, Q1RMT9, Q28969, Q2TAL6, Q2VPJ9, Q4TUC0, Q566C8, Q5BIR3, Q5JTB6, Q5NRP8, Q5RCS3, Q5SPX3, Q5XIX0, Q62600, Q64322, Q7TMJ8, Q7TPD7, Q7TSF4, Q80TT8, Q867D0, Q8BZT7, Q8C8N3, Q8K1T4, Q8K4Z2, Q8MJW9

Diamond homologs: A6YB85, B6ULW4, B6ULW5, B6ULW7, P01376, P01377, P07466, P07467, P07469, P0C8A2, P0C8A3, P11477, P12838, P28309, P28310, P28311, P28312, P50704, P50705, P50706, P50707, P50708, P50709, P50711, P50712, P50713, P50714, P50716, P60030, P60031, P60032, P82106, P82271, P82319, P82320, Q01523, Q01524, Q3L180, Q45VN2, Q4JEI2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

405 predictions. Top by Δscore:

Variant	Effect	Δscore
8:6938222:TTA:T	donor_loss	0.9900
8:6938224:A:AC	donor_gain	0.9900
8:6938224:ACA:A	donor_loss	0.9900
8:6938225:C:CG	donor_gain	0.9900
8:6938225:CA:C	donor_gain	0.9900
8:6938225:CAG:C	donor_gain	0.9900
8:6938225:CAGAT:C	donor_gain	0.9900
8:6936729:TGAA:T	donor_gain	0.9800
8:6938220:ACTT:A	donor_loss	0.9800
8:6938225:CAGA:C	donor_gain	0.9800
8:6938220:A:AC	donor_gain	0.9600
8:6938221:C:CC	donor_gain	0.9600
8:6938217:GTTAC:G	donor_loss	0.9500
8:6938218:TTACT:T	donor_loss	0.9500
8:6938219:TACTT:T	donor_loss	0.9500
8:6936142:C:CC	acceptor_gain	0.9300
8:6936138:GAGCC:G	acceptor_loss	0.9200
8:6936139:AGCC:A	acceptor_loss	0.9200
8:6936141:CCTG:C	acceptor_loss	0.9200
8:6936142:C:CA	acceptor_loss	0.9200
8:6936143:T:G	acceptor_loss	0.9200
8:6936778:T:TA	donor_gain	0.9100
8:6936907:GTGAC:G	acceptor_loss	0.8700
8:6936908:TGACC:T	acceptor_loss	0.8700
8:6936909:GACCT:G	acceptor_loss	0.8700
8:6936910:AC:A	acceptor_loss	0.8700
8:6936911:CC:C	acceptor_loss	0.8700
8:6936912:C:A	acceptor_loss	0.8700
8:6936913:T:A	acceptor_loss	0.8700
8:6937061:ATTGG:A	donor_gain	0.8700

AlphaMissense

618 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:6936047:G:C	F89L	0.955
8:6936047:G:T	F89L	0.955
8:6936049:A:G	F89L	0.955
8:6936069:C:G	C82S	0.941
8:6936070:A:T	C82S	0.941
8:6936036:C:G	C93S	0.940
8:6936037:A:T	C93S	0.940
8:6936099:C:G	C72S	0.937
8:6936100:A:T	C72S	0.937
8:6936039:C:G	C92S	0.936
8:6936040:A:T	C92S	0.936
8:6936099:C:T	C72Y	0.933
8:6936114:C:G	C67S	0.931
8:6936115:A:T	C67S	0.931
8:6936120:C:G	C65S	0.929
8:6936121:A:T	C65S	0.929
8:6936036:C:T	C93Y	0.928
8:6936039:C:T	C92Y	0.924
8:6936114:C:T	C67Y	0.923
8:6936075:C:A	G80V	0.922
8:6936048:A:C	F89C	0.908
8:6936115:A:G	C67R	0.905
8:6936076:C:A	G80W	0.903
8:6936120:C:T	C65Y	0.903
8:6936069:C:T	C82Y	0.902
8:6936121:A:G	C65R	0.902
8:6936070:A:G	C82R	0.900
8:6936075:C:T	G80E	0.900
8:6936098:G:C	C72W	0.900
8:6936035:G:C	C93W	0.899

dbSNP variants (sampled 300 via entrez): RS1000136823 (8:6940135 G>C), RS1000426606 (8:6936426 G>A,C), RS1000485794 (8:6937994 T>C), RS1001359090 (8:6939870 A>G), RS1001627521 (8:6939778 G>A), RS1001752239 (8:6939164 C>G), RS1001870335 (8:6936372 C>A,G,T), RS1002270489 (8:6936607 G>A), RS1002423242 (8:6937053 C>T), RS1003142065 (8:6935570 A>G,T), RS1003249204 (8:6935746 G>A), RS1003429792 (8:6938303 C>G,T), RS1004035314 (8:6938475 CGTCTACTTTG>C), RS1004820017 (8:6936645 T>A,C), RS1004948702 (8:6939885 T>C)

Disease associations

OMIM: gene MIM:601157 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003542_163	Night sleep phenotypes	7.000000e-07
GCST009269_9	Dental caries (decayed and filled deciduous teeth)	5.000000e-06
GCST90002379_106	Basophil count	2.000000e-21
GCST90002380_51	Basophil percentage of white cells	8.000000e-19
GCST90002393_75	Monocyte count	5.000000e-13
GCST90002394_315	Monocyte percentage of white cells	4.000000e-17

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases expression, affects cotreatment	3
Tretinoin	affects cotreatment, increases expression	3
GSK-J4	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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