DEFB126

Summary

DEFB126 (defensin beta 126, HGNC:15900) is a protein-coding gene on chromosome 20p13, encoding Beta-defensin 126 (Q9BYW3). Highly glycosylated atypical beta-defensin involved in several aspects of sperm function.

Defensins are cysteine-rich cationic polypeptides that are important in the immunologic response to invading microorganisms. The antimicrobial protein encoded by this gene is secreted and is a member of the beta defensin protein family. Beta defensin genes are found in several clusters throughout the genome, with this gene mapping to a cluster at 20p13. The encoded protein is highly similar to an epididymal-specific secretory protein (ESP13.2) from cynomolgus monkey. Mutation of this gene is associated with impaired sperm function.

Source: NCBI Gene 81623 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 15 total
• MANE Select transcript: NM_030931

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15900
Approved symbol	DEFB126
Name	defensin beta 126
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	bA530N10.1, DEFB-26
Ensembl gene	ENSG00000125788
Ensembl biotype	protein_coding
OMIM	620131
Entrez	81623

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000382398, ENST00000542572

RefSeq mRNA: 2 — MANE Select: NM_030931 NM_001412225, NM_030931

CCDS: CCDS12990

Canonical transcript exons

ENST00000382398 — 2 exons

Exon	Start	End
ENSE00000858522	145415	145751
ENSE00001491976	142590	142686

Expression profiles

Bgee: expression breadth broad, 49 present calls, max score 99.32.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.1542 / max 1928.3823, expressed in 8 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182985	1.1128	7
182984	0.0232	2
182983	0.0114	2
208957	0.0068	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cauda epididymis	UBERON:0004360	99.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.47	gold quality
corpus epididymis	UBERON:0004359	95.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.33	gold quality
sperm	CL:0000019	75.61	silver quality
male germ cell	CL:0000015	75.11	silver quality
caput epididymis	UBERON:0004358	63.27	gold quality
seminal vesicle	UBERON:0000998	56.62	silver quality
decidua	UBERON:0002450	56.55	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
lower lobe of lung	UBERON:0008949	52.34	silver quality
ileal mucosa	UBERON:0000331	51.41	silver quality
pancreatic ductal cell	CL:0002079	51.38	silver quality
deltoid	UBERON:0001476	50.72	gold quality
epithelial cell of pancreas	CL:0000083	49.70	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
quadriceps femoris	UBERON:0001377	49.05	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
oviduct epithelium	UBERON:0004804	48.62	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
tibialis anterior	UBERON:0001385	48.38	silver quality
vastus lateralis	UBERON:0001379	48.25	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.79

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 9)

• Analyses restricted to glioblastoma (n = 254) yielded significant associations for the SELP, DEFB126/127, SERPINI1, and LY96 genetic regions. (PMID:19423540)
• DEFB126 genotype and lectin binding were correlated with sperm performance in the penetration assays. (PMID:21775668)
• This review shows how DEFB126 is critical for efficient transport of sperm in the female reproductive tract, preventing their recognition by the female immune system. (PMID:22710670)
• These results demonstrate that the DEFB126 core peptide has critical functions in parallel to its C-terminal tail by showing LPS-binding activity, anti-inflammatory effects and intracellular regulatory function. In addition, DEFB126 displays antimicrobial activity against E. coli, S. aureus, and C. elegans. (PMID:23229569)
• Data indicate a significant contribution of the frame-shift polymorphism of defensin beta 126 (DEFB126) rs11467497 to male infertility. (PMID:25721098)
• It is a immune component extensively expressed in mucosa and epidermis, which are responsible for the first line of host defense. (PMID:30529003)
• The role of DEFB126 variation in male infertility and medically assisted reproduction technique outcome. (PMID:31474436)
• Beta-defensin126 is correlated with sperm motility in fertile and infertile mendagger. (PMID:31504198)
• DEFB126 polymorphisms and association with idiopathic asthenozoospermia in China. (PMID:35381696)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Beta-defensin 126 — Q9BYW3 (reviewed: Q9BYW3)

Alternative names: Beta-defensin 26, Defensin, beta 126, Epididymal secretory protein 13.2, HBD26

All UniProt accessions (2): Q9BYW3, A0A384MDP8

UniProt curated annotations — full annotation on UniProt →

Function. Highly glycosylated atypical beta-defensin involved in several aspects of sperm function. Facilitates sperm transport in the female reproductive tract and contributes to sperm protection against immunodetection; both functions are probably implicating the negative surface charge provided by its O-linked oligosaccharides in the sperm glycocalyx. Involved in binding of sperm to oviductal epithelial cells to form a sperm reservoir until ovulation. Release from the sperm surface during capacitation and ovaluation by an elevation of oviductal fluid pH is unmasking other surface components and allows sperm to penetrate the cumulus matrix and bind to the zona pellucida of the oocyte. In vitro has antimicrobial activity and may inhibit LPS-mediated inflammation.

Subunit / interactions. Homodimer or homooligomer; disulfide-linked.

Subcellular location. Secreted.

Tissue specificity. High-level and epididymis-specific expression. Expression is down-regulated in infertile men.

Post-translational modifications. O-glycosylated; glycans contain alpha(2,3)-linked sialic acids.

Disease relevance. May be involved in infertility. Homozygosity for frameshift truncating mutations are associated with reduced sperm O-linked glycan content, impaired sperm mobility and a reduced live birth rate. However, for one common mutation the change in sperm sialic acid levels has been challenged.

Similarity. Belongs to the beta-defensin family.

RefSeq proteins (2): NP_001399154, NP_112193* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR050544	Beta-defensin	Family

UniProt features (8 total): disulfide bond 4, signal peptide 1, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYW3-F1	72.71	0.08

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 (4): 27–58, 34–52, 38–59, 72

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1461957	Beta defensins
R-HSA-1461973	Defensins

MSigDB gene sets: 34 (showing top): GOBP_SINGLE_FERTILIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_HUMORAL_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_GRAM_NEGATIVE_BACTERIUM, GOBP_FERTILIZATION, GOBP_DEFENSE_RESPONSE_TO_BACTERIUM, GOBP_RESPONSE_TO_BACTERIUM, GOBP_ANTIMICROBIAL_HUMORAL_IMMUNE_RESPONSE_MEDIATED_BY_ANTIMICROBIAL_PEPTIDE, PRC2_SUZ12_UP.V1_DN, PTEN_DN.V2_UP, REACTOME_ANTIMICROBIAL_PEPTIDES, GSE13484_3H_UNSTIM_VS_YF17D_VACCINE_STIM_PBMC_UP

GO Biological Process (5): single fertilization (GO:0007338), defense response to Gram-negative bacterium (GO:0050829), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), defense response (GO:0006952), defense response to bacterium (GO:0042742)

GO Molecular Function (0):

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Defensins	1
Antimicrobial peptides	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
fertilization	1
defense response to bacterium	1
antimicrobial humoral response	1
response to stress	1
defense response	1
response to bacterium	1
cellular anatomical structure	1

Protein interactions and networks

STRING

430 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DEFB126	DEFB118	Q96PH6	749
DEFB126	DEFB127	Q9H1M4	720
DEFB126	A0A0G2JN59	A0A0G2JN59	697
DEFB126	DEFB114	Q30KQ6	667
DEFB126	DEFB129	Q9H1M3	645
DEFB126	DEFB128	Q7Z7B8	640
DEFB126	DEFB106A	Q8N104	603
DEFB126	DEFB113	Q30KQ7	580
DEFB126	CRISP1	P54107	575
DEFB126	DEFB125	Q8N687	560
DEFB126	DEFB1	P60022	553
DEFB126	DEFB116	Q30KQ4	553
DEFB126	DEFB105A	Q8NG35	552
DEFB126	DEFB121	Q5J5C9	543
DEFB126	EPPIN	O95925	541

IntAct

5 interactions, top by confidence:

A	B	Type	Score
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (2): DEFB126 (Affinity Capture-MS), DEFB126 (Affinity Capture-MS)

ESM2 similar proteins: A4H220, A4H221, A4H222, A4H223, A4H238, A4H239, A4H240, A4H241, A4H243, A4H244, A4H245, A4H257, A4H258, A4H259, A4H260, O54947, P59647, P97808, Q17R60, Q30KK0, Q30KK1, Q30KK2, Q30KK3, Q30KK9, Q30KL1, Q30KQ4, Q32ZH2, Q3MIW9, Q5FVR0, Q5XI99, Q62170, Q64294, Q6MG22, Q6U7R4, Q7TST5, Q7Z7G0, Q8JZQ0, Q8N687, Q8R183, Q95152

Diamond homologs: A4H243, A4H244, A4H245, Q30KK2, Q32P86, Q8BVC1, Q9BEE3, Q9BYW3, A4H255, A4H225, A4H226, A4H227, A4H228, Q30KK4, Q30KK8, Q30KT5, Q5J602, Q8K3I8, Q8N690, Q8NES8, A4H223, Q95LI0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	11
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

364 predictions. Top by Δscore:

Variant	Effect	Δscore
20:145489:G:GG	donor_gain	0.9600
20:145410:TTCA:T	acceptor_loss	0.9200
20:145411:TCA:T	acceptor_loss	0.9200
20:145412:CAGG:C	acceptor_loss	0.9200
20:145413:AGG:A	acceptor_loss	0.9200
20:142631:G:GT	donor_gain	0.8700
20:142681:TCTC:T	donor_gain	0.8700
20:145488:T:G	donor_gain	0.8700
20:142742:G:GT	donor_gain	0.8600
20:145577:A:AG	acceptor_gain	0.8500
20:145578:G:GG	acceptor_gain	0.8500
20:145485:GCAT:G	donor_gain	0.8400
20:145493:A:G	donor_gain	0.8300
20:142682:CTCAG:C	donor_loss	0.8200
20:142683:TCAG:T	donor_loss	0.8200
20:142684:CAGGT:C	donor_loss	0.8200
20:142685:AG:A	donor_loss	0.8200
20:142686:G:GC	donor_loss	0.8200
20:142687:GTA:G	donor_loss	0.8200
20:142688:T:A	donor_loss	0.8200
20:145464:G:GT	donor_gain	0.8100
20:145492:A:AG	donor_gain	0.7900
20:142751:GTTTC:G	donor_gain	0.7800
20:142752:TTTCT:T	donor_gain	0.7800
20:142755:C:CG	donor_gain	0.7700
20:142764:C:A	donor_gain	0.7600
20:142800:GGC:G	donor_gain	0.7600
20:145414:GGTA:G	acceptor_gain	0.7600
20:145413:A:AG	acceptor_gain	0.7500
20:145414:G:GG	acceptor_gain	0.7500

AlphaMissense

719 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:145456:T:A	C34S	0.996
20:145457:G:C	C34S	0.996
20:145528:T:A	C58S	0.996
20:145529:G:C	C58S	0.996
20:145435:T:A	C27S	0.995
20:145436:G:C	C27S	0.995
20:145451:G:A	G32E	0.995
20:145510:T:A	C52S	0.995
20:145511:G:C	C52S	0.995
20:145531:T:A	C59S	0.995
20:145532:G:C	C59S	0.995
20:145468:T:A	C38S	0.994
20:145469:G:C	C38S	0.994
20:145450:G:A	G32R	0.993
20:145450:G:C	G32R	0.993
20:145528:T:C	C58R	0.993
20:145530:C:G	C58W	0.993
20:145456:T:C	C34R	0.990
20:145529:G:A	C58Y	0.990
20:145435:T:C	C27R	0.989
20:145457:G:A	C34Y	0.989
20:145468:T:C	C38R	0.989
20:145437:T:G	C27W	0.988
20:145451:G:T	G32V	0.988
20:145531:T:C	C59R	0.987
20:145510:T:C	C52R	0.986
20:145458:C:G	C34W	0.985
20:145512:C:G	C52W	0.985
20:145532:G:A	C59Y	0.985
20:145511:G:A	C52Y	0.984

dbSNP variants (sampled 300 via entrez): RS1000298173 (20:145189 T>A), RS1002247699 (20:140832 A>G), RS1002505884 (20:143205 G>A), RS1002988452 (20:142881 C>A,T), RS1003357974 (20:144370 C>T), RS1004424826 (20:142363 C>T), RS1004528375 (20:142391 G>A), RS1005125375 (20:142831 C>T), RS1005461813 (20:144353 G>A), RS1006204754 (20:143987 T>C), RS1007735663 (20:145173 C>G,T), RS1008326938 (20:143420 A>G), RS1008994534 (20:142257 A>G), RS1009215751 (20:141470 T>C), RS1009439721 (20:141858 C>A,T)

Disease associations

OMIM: gene MIM:620131 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

3 total (human), top 3 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	1
Cyclosporine	increases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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