|ZFIN ID: ZDB-PUB-151223-2|
Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate
Liu, H., Leslie, E.J., Jia, Z., Smith, T., Eshete, M., Butali, A., Dunnwald, M., Murray, J., Cornell, R.A.
|Source:||Human molecular genetics 25(4): 766-76 (Journal)|
|Registered Authors:||Cornell, Robert|
|PubMed:||26692521 Full text @ Hum. Mol. Genet.|
Liu, H., Leslie, E.J., Jia, Z., Smith, T., Eshete, M., Butali, A., Dunnwald, M., Murray, J., Cornell, R.A. (2016) Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate. Human molecular genetics. 25(4):766-76.
ABSTRACTNon-syndromic (NS) cleft lip with or without cleft palate (CL/P) is a common disorder with a strong genetic underpinning. Genome wide association studies have detected common variants associated with this disorder, but a large portion of the genetic risk for NSCL/P is conferred by unidentified rare sequence variants. Mutations in IRF6 (Interferon Regulatory Factor 6) and GRHL3 (Grainyhead like 3) cause Van der Woude syndrome, which includes CL/P. Both genes encode members of a regulatory network governing periderm differentiation in model organisms. Here we report that Krüppel-like factor 17 (Klf17), like Grhl3, acts downstream of Irf6 in this network in zebrafish periderm. Although Klf17 expression is absent from mammalian oral epithelium, a close homolog, Klf4, is expressed in this tissue and is required for the differentiation of epidermis. Chromosome configuration capture and reporter assays indicated that IRF6 directly regulates an oral-epithelium enhancer of KLF4. To test whether rare missense variants of KLF4 contribute risk for NSCL/P, we sequenced KLF4 in approximately 1000 NSCL/P cases and 300 controls. By one statistical test, missense variants of KLF4 as a group were enriched in cases versus controls. Moreover, two patient-derived KLF4 variants disrupted periderm differentiation upon forced expression in zebrafish embryos, suggesting they have dominant negative effect. These results indicate rare NSCL/P risk variants can be found in members of the gene regulatory network governing periderm differentiation.