Table 1.
Genetic associations in Crohn's disease with a relevance in the specialized antimicrobial producing Paneth cell
| Factor | Full gene name | Core functions | Relevance in Paneth cell |
|---|---|---|---|
| Factors with a direct link to Paneth cell function | |||
| NOD2/CARD15* | Nucleotide-binding oligomerization domain-containing protein 2/caspase recruitment domain-containing protein 15 | Intracellular PRR sensing bacterial muramyldipeptide | NOD2 is involved in the expression of Paneth cell defensins and the activation of innate antimicrobial defense strategies (Begue et al, 2006). Carriers of a frameshift risk variant have been reported to exhibit particularly low Paneth cell α-defensin levels (Bevins et al, 2009; Wehkamp et al, 2005b). |
| Atg16L1* | Autophagy related 16-like 1 (S. cerevisiae) | Part of a protein complex involved in autophagy, the major degradation system of cytoplasmatic components | ATG16L1 is involved in the granule exocytosis pathway and respectively the secretion of Paneth cell AMPs. Patients carrying the associated risk variants display Paneth cell abnormalities (Cadwell et al, 2008) |
| XBP1 | X-box binding protein 1 | Important transcription factor in the ER stress response as well as secretory cell development and maintenance | XBP1 deletion results in apoptotic Paneth cell loss and reduced antimicrobial activity. In addition to the association of common SNPs, the gene also exhibits rare hypomorphic non-synonymus variants in IBD patients (Kaser et al, 2008) |
| LRP6* | Low density lipoprotein related receptor 6 | Wnt Co-receptor, R-Spondin receptor and LGR interaction partner with an important role in β-catenin dependent Wnt | LRP6 expression levels are linked to those of Paneth cell HD5 in vitro. The receptor's mRNA is furthermore reduced in small intestinal CD and an early onset associated non-synonymous risk variant precedes even further reduced levels of HDs (Koslowski et al, 2012) |
| TCF7L2* | Transcription factor 7-like 2 (T-cell specific, HMG-box), also known as TCF4 | Transcription factor and interaction partner of β-catenin. Important regulator of Wnt target genes | TCF7L2 is reduced in and genetically associated with small intestinal CD. It binds the promoter region of HD5/6 and regulates the α-defensins transcriptional expression (Koslowski et al, 2009b; Wehkamp et al, 2007) |
| Factors with a hypothesized role in diminished Paneth cell function in CD patients | |||
| Lef1 | Lymphoid enhancer-binding factor 1 | Transcription factor and interaction partner of β-catenin. Important regulator of Wnt target genes and associated with CD (Dinu et al, 2012). It's role in canonical Wnt would support a potential involvement in Paneth cell function and in particular in the regulation of the α-defensins HD5 and HD6 | A CDH1 CD risk haplotype precedes increased cytoplasmic E-cadherin likely due to a truncated form of the protein. This protein version also promotes impaired β-catenin localisation in vitro and might therefore be relevant for the canonical Wnt activity in Paneth cells (Muise et al, 2009) |
| CDH1 | Cadherin-1 or epithelial cadherin (E-cadherin) | A calcium-dependent cell–cell adhesion glycoprotein involved in mechanisms regulating epithelial cell adhesion, mobility and proliferation | |
| KCNN4* | Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4 | Part of a voltage-independent potassium (K(+)) channel activated by intracellular calcium (Ca(2+)) | The genetically associated KCNN4 encodes KCa3.1, which is found in Paneth cells. NOD2 risk variant carriers also exhibit reduced KCNN4 mRNA (Simms et al, 2010). In mice, a Ca(2+)-activated K(+) channel modulates Paneth cell secretion (Ayabe et al, 2002) which might allow to hypothesize a similar relevance of KCa3.1 in humans |
*
Associations are known to be stronger or specific to the small intestinal Crohn's disease subphenotype.