DEFA5 – Crohn disease

DEFA5 encodes human alpha‐defensin 5, a key antimicrobial peptide produced by Paneth cells that is critical for intestinal innate immunity. Several independent multi‐patient studies have reported an association between DEFA5 and Crohn disease (PMID:15479689), supporting its role in mucosal defense and disease pathogenesis.

Genetic evidence includes gene expression analyses and SNP association studies. For instance, one study evaluated 385 Crohn disease probands alongside patients with ulcerative and indeterminate colitis and identified significant odds ratios for DEFA5 polymorphisms (PMID:18394979). In another investigation using surgical specimens from four patients, DEFA5 was among a set of genes consistently upregulated in diseased colonic tissues (PMID:18084881).

Although detailed segregation data are limited, the replication of differential DEFA5 expression in multiple independent cohorts substantiates its genetic implication in Crohn disease. The concurrence of these findings across case series, gene expression profiles, and association analyses provides moderate but consistent support for the gene–disease relationship.

Functional studies further reinforce the clinical association. Experimental evidence has demonstrated that the conserved salt bridge within HD5 is crucial for its precursor processing and proteolytic stability, ensuring proper antimicrobial activity (PMID:18499668). Additional analyses probing the dimer interface have shown that alterations in hydrophobic contacts can disrupt function, suggesting a mechanistic link to impaired mucosal barrier function (PMID:22573326).

Collectively, the genetic findings and functional assays indicate that disruptions in DEFA5 expression or processing may contribute to the compromised intestinal barrier observed in Crohn disease. While explicit single‐nucleotide variant details in HGVS format were not provided, the recurrent associations and mechanistic insights together strengthen the biological plausibility of this relationship.

It is also noteworthy that, while additional evidence exists from related studies on Paneth cell defensins, the cumulative data for DEFA5 specifically meet moderate ClinGen criteria. This integrated view supports its role as a risk factor and potential biomarker in Crohn disease.

Key Take‑home: The convergence of multi‐patient genetic associations and robust functional studies establishes DEFA5 as an important contributor to Crohn disease pathogenesis, with significant implications for diagnostics, patient stratification, and therapeutic development.

References

• Gut • 2004 • NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression PMID:15479689
• Journal of medicine • 2004 • Gene expression profiles of late colonic Crohn's disease PMID:18084881
• Digestive and liver disease • 2008 • Single nucleotide polymorphisms in human Paneth cell defensin A5 may confer susceptibility to inflammatory bowel disease in a New Zealand Caucasian population PMID:18394979
• The Journal of biological chemistry • 2008 • The conserved salt bridge in human alpha-defensin 5 is required for its precursor processing and proteolytic stability PMID:18499668
• The Journal of biological chemistry • 2012 • Functional determinants of human enteric α-defensin HD5: crucial role for hydrophobicity at dimer interface PMID:22573326

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