DEFA6 – Crohn Disease

This summary evaluates the association between DEFA6 and Crohn disease by synthesizing evidence from multi‐patient studies. Two independent studies have implicated dysregulation of alpha‐defensin expression in Crohn disease, suggesting that altered DEFA6 expression contributes to impairment of the gut mucosal defense. The first study demonstrated that patients with Crohn disease, especially those with NOD2 mutations, exhibit diminished expression of Paneth cell defensins, including the product of DEFA6 (PMID:15479689). The second study, using gene expression profiling of colonic tissues from Crohn disease patients, further identified DEFA6 as one of several genes with differential expression in diseased compared to uninvolved tissues (PMID:18084881).

Assessment of the clinical validity places the DEFA6–Crohn disease association in the Limited category. This determination is based on evidence derived solely from expression studies and profiling experiments without reported case‐level deleterious variants or clear segregation data (45 patients in one study and a cohort of four patients in another, PMID:15479689 and PMID:18084881 respectively).

The genetic evidence is primarily indirect, arising from comparative gene expression rather than identification of pathogenic coding variants. No specific HGVS‐coded variants have been described for DEFA6 in these studies; hence, variant‐level evidence remains absent. The inheritance mode for Crohn disease is complex, and while multiple genes are implicated, the evidence for DEFA6 is limited to expression differences with no clear segregation of mutant alleles among affected families.

Functional studies indicate that reduced expression of alpha‐defensins, including DEFA6, may compromise the intestinal antimicrobial barrier. Immunohistochemistry and mRNA quantification in Crohn disease tissues consistently showed lower expression levels in affected regions, supporting a mechanistic role in mucosal immunity dysfunction. Although robust direct experiments (e.g. rescue assays) are lacking, the concordance between altered gene expression and the clinical phenotype provides moderate functional evidence supporting the association.

While the association does not reach the level required for definitive clinical actionability, the combined genetic and functional evidence highlights a potential contribution of DEFA6 to Crohn disease pathogenesis. Future studies focusing on case‐level variant identification and detailed functional analyses may further refine the clinical validity of this association. Key take‑home: The observed differential expression of DEFA6 in Crohn disease underscores its potential as a biomarker and a target for elucidating mechanisms of intestinal mucosal immunity.

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

Evidence Based Scoring (AI generated)