Alternative titles; symbols
HGNC Approved Gene Symbol: DEFA6
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38): 8:6,924,697-6,926,076 (from NCBI)
The DEFA6 gene encodes an alpha-defensin expressed in Paneth cells that is thought to protect the small intestine against invasion by diverse enteric pathogens (Chu et al., 2012).
Defensins are a family of small cationic peptides that constitute 5 to 10% of protein in neutrophils and are shown to be a major component of granular leukocytes. By cloning the cDNA from a human small intestine library, Jones and Bevins (1993) identified a new member of the defensin family, designated defensin-6. They identified the peptide by the conserved 5-prime nucleotide sequence common to previously characterized cDNAs. By Northern blot and PCR analysis, DEF6 mRNA was found exclusively in the small intestine. Isotopic in situ hybridization further localized the mRNA to the Paneth cells at the base of crypts of Lieberkuhn. Defensin-5 (600472) was previously detected in Paneth cells. The presence of abundant defensin mRNA in human Paneth cells supports the notion that these epithelial cells may play a key role in host defense of human bowel.
Mallow et al. (1996) showed that defensin-6 has a genomic organization similar to defensin-5, and that the 2 genes have a striking pattern of sequence similarity localized chiefly in their proximal 5-prime flanking regions.
By analysis of a panel of human/hamster hybrids, Bevins et al. (1996) localized both the DEF5 and the DEF6 gene to chromosome 8. By Southern blot analysis of DNA from cell lines that contained either chromosome 8 deletions or duplications and fluorescence in situ hybridization, they further localized the genes to 8pter-p21. The hematopoietic defensin genes DEF1 (125220), DEF3 (604522), and DEF4 (601157) had previously been mapped to the same region. This mapping information and sequence comparison of the human hematopoietic and enteric defensin genes suggested a mechanism of their evolution, namely an early duplication of a primordial defensin gene yielding the ancestral genes of present-day DEF5 and DEF6. The authors' model further suggested that a subsequent unequal meiotic crossover event generated an additional gene composed of a hybrid of sequences from the 2 parental genes, and that this hybrid gene then served as the ancestor to present day hematopoietic defensin genes.
Mallow et al. (1996) described the patterns of expression of the 2 defensins during both stages of development and regionally in the intestine. The pattern of expression coincided with the previously described appearance of Paneth cells. In situ hybridization analyses localized expression of enteric defensin mRNA to Paneth cells at 24 weeks of gestation, as is seen in the newborn term infant and the adult. Consistent with earlier morphologic studies, the ratio of Paneth cell number per crypt was reduced in samples at 24 weeks of gestation compared with the adult. Mallow et al. (1996) speculated that low levels of enteric defensin expression in the fetus may be characteristic of an immaturity of local defense, which is thought to predispose infants born prematurely to infection from intestinal microorganisms.
Wilson et al. (1999) demonstrated that the activity of alpha-defensins is regulated by matrilysin (178990).
Chu et al. (2012) reported that human alpha-defensin 6 affords protection against invasion by enteric bacterial pathogens in vitro and in vivo. After stochastic binding to bacterial surface proteins, alpha-defensin 6 undergoes ordered self-assembly to form fibrils and nanonets that surround and entangle bacteria. This self-assembly mechanism occurs in vivo, requires histidine-27, and is consistent with x-ray crystallography data. Chu et al. (2012) concluded that their findings supported a key role for human alpha-defensin 6 in protecting the small intestine against invasion by diverse enteric pathogens and may explain the conservation of HD6 throughout Hominidae evolution.
Bevins, C. L., Jones, D. E., Dutra, A., Schaffzin, J., Muenke, M. Human enteric defensin genes: chromosomal map position and a model for possible evolutionary relationships. Genomics 31: 95-106, 1996. [PubMed: 8808285] [Full Text: https://doi.org/10.1006/geno.1996.0014]
Chu, H., Pazgier, M., Jung, G., Nuccio, S.-P., Castillo, P. A., de Jong, M. F., Winter, M. G., Winter, S. E., Wehkamp, J., Shen, B., Salzman, N. H., Underwood, M. A., Tsolis, R. M., Young, G. M., Lu, W., Lehrer, R. I., Baumler, A. J., Bevins, C. L. Human alpha-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. Science 337: 477-481, 2012. [PubMed: 22722251] [Full Text: https://doi.org/10.1126/science.1218831]
Jones, D. E., Bevins, C. L. Defensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the human bowel. FEBS Lett. 315: 187-192, 1993. [PubMed: 8417977] [Full Text: https://doi.org/10.1016/0014-5793(93)81160-2]
Mallow, E. B., Harris, A., Salzman, N., Russell, J. P., DeBerardinis, R. J., Ruchelli, E., Bevins, C. L. Human enteric defensins: gene structure and developmental expression. J. Biol. Chem. 271: 4038-4045, 1996. [PubMed: 8626737] [Full Text: https://doi.org/10.1074/jbc.271.8.4038]
Wilson, C. L., Ouellette, A. J., Satchell, D. P., Ayabe, T., Lopez-Boado, Y. S., Stratman, J. L., Hultgren, S. J., Matrisian, L. M., Parks, W. C. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286: 113-117, 1999. [PubMed: 10506557] [Full Text: https://doi.org/10.1126/science.286.5437.113]