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Correspondence to Professor Runjan Chetty, Department of Histopathology, Brighton and Sussex University Hospitals NHS Trust, Brighton BN2 5BE, UK; [email protected]
Gene structure and protein
The Transducin-like enhancer of split 1 (TLE 1) gene belongs to a family of four genes, is located on chromosome 9q21 and is consists of 19 exons. TLE1 protein is the human homologue of the Drosophila groucho protein. It encodes a non-DNA binding, 770 amino acid transcriptional protein that serves as a co-repressor of other transcription factors and signalling pathways. TLE1 protein forms homo-oligomers and hetero-oligomers with several proteins, and after binding, it acts to inhibit transcriptional activity, especially in the Wnt signalling pathway where it interacts with β-catenin and T-cell factor.
Physiological role
TLE1 protein plays a normal, physiological role in several processes including during embryogenesis, haematopoiesis, epithelial differentiation, segmentation and neuronal/eye development (see figure 1).
TLE 1 in disease
Non-cancer
See figure 2.
Inflammation
The nuclear factor-kappa B (NF-κB) signalling pathway controls the immune response; hence, it plays a role in inflammation. TLE 1 represses NF-κB activity. Thus, the loss of TLE1 results in excessive activation of NF-κB–mediated inflammatory pathways associated with increased expression of inflammatory cytokines and chemokines in the skin, lung and intestine.1 Interactions of TLE1 and nucleotide-binding oligomerisation domain-containing protein 2 (NOD2) are involved with inflammatory bowel disease. NOD2 gene was the first susceptibility gene identified in Crohn’s disease (CD). Nimmo et al 2 suggested that TLE1 can regulate NOD2 functions. They realised single nucleotide polymorphisms (SNP) in TLE1 (intronic SNP rs6559629) result in a TLE risk allele which unmasks the mutant NOD2 resulting in CD (ileal phenotype).
Diabetes mellitus (type 2)
TLE1 is a regulator of pancreatic islet β-cell identity. Armour et al 3 indicated that reduced expression of TLE1 in islet cells is inversely correlated with ⍺/β cell ratio. Decreased TLE1 causes an increase in glucagon gene mRNA and misexpression of glucagon in islet cells, which leads to a loss of cellular identity potentially leading to β-cell to ⍺-cell conversion.
Postnatal microcephaly
In postnatal microcephaly, although the child has a normal head size at birth, there is a subsequent deceleration of the head circumference caused by mutations in genes responsible for the development of the forebrain. Mutations in genes like CASK