DEFB1 (defensin, beta 1)

2010-05-01   Ernesto Prado Montes de Oca 

Identity

HGNC
LOCATION
8p23.1
LOCUSID
ALIAS
BD1,DEFB-1,DEFB101,HBD1

DNA/RNA

Atlas Image
Figure 1. DEFB1 gene. The diagram shows pre-propeptide coding sequence (black rectangles) and unstranslated regions (blue rectangles). Signal peptide coding sequence is comprised of 60 bases. Mature peptide coding sequence spans 144 bases (www.ensembl.org). The pro-peptide segment is in exon 1 and not in exon 2 as in the rest of beta-defensins known to date (Pazgier et al., 2006).

Description

DEFB1 is a gene composed of 2 exons and a ~7 kb intron. DEFB1 spans 7488 bp, two exons and one intron of 6962 bp (Liu et al., 1997).

Transcription

The transcript is of 207 nt (www.kegg.org). No variants are produced by alternative splicing, the entire mature peptide coding sequence is in exon 1, however several hBD-1 amino-terminal processed forms are found in urine (Valore et al., 1998), probably cleaved by chymotrypsin (Zucht et al., 1998) or matrix metalloproteinase 7 (matrylisin) (Wilson et al., 2009) each showing different microbicidal potencies (Valore et al., 1998). The functions and tissue of origin of these processed forms are unknown (Prado-Montes de Oca, 2010).

Pseudogene

None reported. DEFB1 is considered as a unique copy gene, although rare duplicons in some individuals have been reported (Linzmeier et al., 2005).

Proteins

Note

Human beta-defensins are produced mainly by various epithelia and secreted in mature forms by the producing cells. The hBD-1 shows three disulfide bridges (with the pro-peptide nomenclature) are formed at cysteines 37-66 (1-5), 44-59 (2-4) and 49-67 (3-6). The disulfide bridge pattern on cysteines 1-5, 2-4 and 3-6 is a hallmark of beta-defensins (Prado-Montes de Oca, 2010).
Atlas Image
Figure 2. (A) Model of hBD-1 peptide (according to PDB:1IJU, www.pdb.org). (B) Sequence of hBD-1 pro-peptide. Signal peptide sequence (blue), mature peptide (black) with cysteine residues (bold) and disulfide bridges (brackets) are shown.

Description

The prepropeptide has 68 aa and the mature peptide is of 48 amino acids. As quaternary structure hBD-1 shows in vitro dimerization by weak intermolecular salt bridges, but if dimers are formed in vivo or if they perform any different function is unknown (Prado Montes de Oca, 2010).

Expression

The highest concentrations of hBD-1 are found in the kidney (epithelial layes of the loops of Henle, distal tubules, collecting tubes) and female reproductive tract (layers of vagina, ectocervix, endocervix, uterus, fallopian tubes), especially in pregnant women. It is also expressed in astrocytes, mammary gland, cornea, small intestine, gingival tissue, epithelial cells of testis, mature dendritic cells (for a more complete information of DEFB1-expressing cells see www.ebi.ac.uk/microarray-as/atlas and www.ncbi.nlm.nih.gov/geo/).

Localisation

The hBD-1 peptide resides in the cytoplasm of normal cells and in the nucleus of several cancer cells (Bick et al., 2007; Wenghoefer et al., 2008). In normal skin, hBD-1 is localized to the perinuclear region of keratinocytes and in burned skin in dermal glandular structures and hair shafts (Poindexter et al., 2006).

Function

hBD-1 functions as an antimicrobial peptide against viruses as HIV, Av1CF2, Gram-positive and Gram-negative bacteria, Mycobacterium tuberculosis. It functions as a chemoattractant to immature dendritic cells and T cells acts as a tumor suppressor inducing caspase-mediated apoptosis. In addition it could be involved as transcription factor in epithelia reorganization (Prado Montes de Oca, 2010).

Homology

Homolog genes to human beta-defensin 1 are found in Mus musculus (mouse) (Morrison et al., 1998), Pan troglodytes (chimpanzee) (Prado-Montes de Oca et al., 2009), Macaca mulatta (Rhesus monkey), Canis familiaris (dog), Rattus norvegicus (rat), Sus scrofa (pig, named beta defensin 2), Bos taurus (cow, named protein similar to beta defensin) among other species (www.kegg.org; www.ensembl.org).

Mutations

Note

There are 214 annotated polymorphisms in DEFB1, most of them are SNPs (bdSNP build 130, www.genome.ucsc.edu). Insertions and deletions are less frequently found (López Campos and Prado Montes de Oca, in process). There are reports of 10 SNPs in DEFB1 with disease association. The most relevant SNPs are those located on 5 unstranslated region namely -52A (higher HIV load and higher risk of perinatal HIV infection, gastritis, asthma), -44C (atopic dermatitis, chronic obstructive pulmonar disease, Crohns disease, cancer, lepromatous leprosy) and -20 A/G (infections in cystic fibrosis) (gene RIF at www.ncbi.nlm.nih.gov; Prado-Montes de Oca, 2010). The variant -44C correlates with lower constitutive expression and -44G correlates with lower IFN-gamma-dependent induction. This could explain the extremely rare heterozygote advantage in this region (Figuera et al., 2005; Prado Montes de Oca, 2010).
Atlas Image
Figure 3. The 214 polymorphisms annotated in both strands of DEFB1 gene according to UCSC Genome Browser (www.genome.ucsc.edu, hg19, Feb 2009). Most polymorphisms are located in intron (black), fewer are located in UTRs (blue) and exons. Those polymorphisms located in exons could be either synonymous (green) or non-synonymous (red).

Implicated in

Entity name
The 8p23.1 duplication syndrome
Note
Associate with variable phenotype that may include one or more of the following: developmental delay, mild dysmorphism and heart defects (Barber et al., 2010).
Cytogenetics
The 8p23.1 duplication syndrome and copy number variation of the 8p23.1 defensin gene cluster are cytogenetically indistinguishable but distinct at the molecular level (Barber et al., 2010).
Entity name
Copy number variation of the 8p23.1 defensin gene cluster
Note
From 1 to 12 copies of 8p23.1 defensin gene cluster are normally found per diploid genome (Hollox et al., 2003). The null allele is very rare (allele frequency 0.2%) (Hollox et al., 2008). Predisposition to Crohns disease and sporadic prostate cancer is higher at low copy number (Huse et al., 2008) and to psoriasis at high copy number (Hollox, 2008).
Entity name
Oral squamous cell carcinoma (OSCC)
Note
DEFB1 basal expression is 50-fold lower in OSCC, and inducibility is significantly reduced (Wenghoefer et al., 2008). Genotypes in DEFB1 gene tend to loss of heterozygosity in OSCC (Joly et al., 2009).
Entity name
Malignant melanoma
Note
It was found weak evidence that genotype -44 GG in DEFB1 increases risk for malignant melanoma in a Spanish population (OR= 2.78, CI 95%= 0.88-8.82, p=0.08) (Fernandez et al., 2009).
Entity name
Prostate and renal cancers
Note
DEFB1 has been proposed as a tumor suppressor because it promotes cancer cells apoptosis and is absent in most tumor samples (Sun et al., 2006; Bullard et al., 2008). There is a marked down-regulation of DEFB1 in 82% of prostate cancers and 90% of renal cell carcinomas (Donald et al., 2003) and this DEFB1 downregulation is associated with malignancy (Wenghoefer et al., 2008; Pantelis et al., 2009). Furthermore, oncogene PAX2 binds to DEFB1 promoter and suppresses its expression independent of p53 (Bose et al., 2009). Parvalbumin and DEFB1 expression could be useful to differentiate papillary renal cell carcinoma (RCC) from conventional RCC (Young et al., 2003).
Entity name
Leukoplakia
Note
DEFB1 is downregulated 2.5 fold in leukoplakia but their role in the disease, if any, is unknown (Wenghoefer et al., 2008).
Entity name
Several allergic and infectious diseases
Note
For allergic and infectious diseases where DEFB1 is implicated see Prado Montes de Oca, 2010.

Bibliography

Pubmed IDLast YearTitleAuthors
2016706720108p23.1 duplication syndrome differentiated from copy number variation of the defensin cluster at prenatal diagnosis in four new families.Barber JC et al
180919802007Nuclear localization of HBD-1 in human keratinocytes.Bick RJ et al
191189002009PAX2 oncogene negatively regulates the expression of the host defense peptide human beta defensin-1 in prostate cancer.Bose SK et al
178688712008Functional analysis of the host defense peptide Human Beta Defensin-1: new insight into its potential role in cancer.Bullard RS et al
126955532003Cancer-specific loss of beta-defensin 1 in renal and prostatic carcinomas.Donald CD et al
197414262009Human beta-defensins (HBD1 and HBD3) and malignant melanoma susceptibility.Fernandez LP et al
129160162003Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster.Hollox EJ et al
189742632008Defensins and the dynamic genome: what we can learn from structural variation at human chromosome band 8p23.1.Hollox EJ et al
192871492008Copy number variation of beta-defensins and relevance to disease.Hollox EJ et al
185159862008Genetic variants of the copy number polymorphic beta-defensin locus are associated with sporadic prostate cancer.Huse K et al
197029472009Loss of human beta-defensin 1, 2, and 3 expression in oral squamous cell carcinoma.Joly S et al
197124722009Association of a genetic polymorphism (-44 C/G SNP) in the human DEFB1 gene with expression and inducibility of multiple beta-defensins in gingival keratinocytes.Kalus AA et al
160390932005Human defensin gene copy number polymorphisms: comprehensive analysis of independent variation in alpha- and beta-defensin regions at 8p22-p23.Linzmeier RM et al
92686341997The human beta-defensin-1 and alpha-defensins are encoded by adjacent genes: two peptide families with differing disulfide topology share a common ancestry.Liu L et al
95854331998Mouse beta defensin-1 is a functional homolog of human beta defensin-1.Morrison GM et al
188057292009Down regulation and nuclear localization of human beta-defensin-1 in pleomorphic adenomas of salivary glands.Pantelis A et al
170716142007Studies of the biological properties of human beta-defensin 1.Pazgier M et al
166213132006Localization of antimicrobial peptides in normal and burned skin.Poindexter BJ et al
201005912010Human beta-defensin 1: a restless warrior against allergies, infections and cancer.Prado-Montes de Oca E et al
169511662006Human beta-defensin-1, a potential chromosome 8p tumor suppressor: control of transcription and induction of apoptosis in renal cell carcinoma.Sun CQ et al
95414931998Human beta-defensin-1: an antimicrobial peptide of urogenital tissues.Valore EV et al
183468772008Decreased gene expression of human beta-defensin-1 in the development of squamous cell carcinoma of the oral cavity.Wenghoefer M et al
191816622009Differential Processing of {alpha}- and {beta}-Defensin Precursors by Matrix Metalloproteinase-7 (MMP-7).Wilson CL et al
125481662003Beta defensin-1, parvalbumin, and vimentin: a panel of diagnostic immunohistochemical markers for renal tumors derived from gene expression profiling studies using cDNA microarrays.Young AN et al
96820271998Human beta-defensin-1: A urinary peptide present in variant molecular forms and its putative functional implication.Zucht HD et al

Other Information

Locus ID:

NCBI: 1672
MIM: 602056
HGNC: 2766
Ensembl: ENSG00000164825

Variants:

dbSNP: 1672
ClinVar: 1672
TCGA: ENSG00000164825
COSMIC: DEFB1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000164825ENST00000297439P60022

Expression (GTEx)

0
500
1000
1500
2000

Pathways

PathwaySourceExternal ID
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
DefensinsREACTOMER-HSA-1461973
Beta defensinsREACTOMER-HSA-1461957
Antimicrobial peptidesREACTOMER-HSA-6803157

References

Pubmed IDYearTitleCitations
180592662008Psoriasis is associated with increased beta-defensin genomic copy number.233
212488502011Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1.157
117419802002The solution structures of the human beta-defensins lead to a better understanding of the potent bactericidal activity of HBD3 against Staphylococcus aureus.83
125178312003Single-nucleotide polymorphisms (SNPs) in human beta-defensin 1: high-throughput SNP assays and association with Candida carriage in type I diabetics and nondiabetic controls.51
153220102004Proteus mirabilis ZapA metalloprotease degrades a broad spectrum of substrates, including antimicrobial peptides.49
208586042010Measurement methods and accuracy in copy number variation: failure to replicate associations of beta-defensin copy number with Crohn's disease.48
158292972005Correlation between beta-defensin expression and induction profiles in gingival keratinocytes.39
187178212008Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human beta-defensin 1 (HBD-1) expression in the intestinal epithelial cells.38
206738682010A genetic association study of maternal and fetal candidate genes that predispose to preterm prelabor rupture of membranes (PROM).36
215512522011Modulation of human beta-defensin-1 (hBD-1) in plasmacytoid dendritic cells (PDC), monocytes, and epithelial cells by influenza virus, Herpes simplex virus, and Sendai virus and its possible role in innate immunity.36

Citation

Ernesto Prado Montes de Oca

DEFB1 (defensin, beta 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-05-01

Online version: http://atlasgeneticsoncology.org/gene/44352/defb1