Human Molecular Genetics Advance Access published online on November 26, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn381
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Mis-sense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6
1 Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT. UK 2 Dental School, University of Manchester, Oxford Road, Manchester M13 9PT. UK 3 Department of Pediatrics and Interdisciplinary PhD Program in Genetics, University of Iowa, Iowa City, IA. USA 4 Department of Biochemistry, University of Iowa, Iowa City, IA. USA
* Corresponding authors; contact details: E-mail: mike.dixon{at}manchester.ac.uk; Telephone number: +44-161 275 5620; Fax: +44-161 275 5082
Received September 26, 2008; Revised November 10, 2008; Accepted November 10, 2008
Cleft lip and cleft palate are common disorders that occur either as part of a syndrome, where structures other than the lip and palate are affected, or in the absence of other anomalies. Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) are autosomal dominant disorders characterised by combinations of cleft lip, cleft palate, lip pits, skin-folds, syndactyly, and oral adhesions which arise as the result of mutations in interferon regulatory factor 6 (IRF6). IRF6 belongs to a family of transcription factors that share a highly conserved N-terminal, DNA-binding domain and a less well-conserved protein-binding domain. To date, mutation analyses have suggested a broad genotype-phenotype correlation in which mis-sense and non-sense mutations occurring throughout IRF6 may cause VWS; in contrast, PPS-causing mutations are highly associated with the DNA-binding domain, and appear to preferentially affect residues that are predicted to interact directly with the DNA. Nevertheless, this genotype-phenotype correlation is based on analysis of structural models rather than on investigation of the DNA-binding properties of IRF6. Moreover, the effects of mutations in the protein interaction domain have not been analysed. In the current investigation, we have determined the sequence to which IRF6 binds and used this sequence to analyse the effect of VWS- and PPS-associated mutations in the DNA-binding domain of IRF6. In addition, we have demonstrated that IRF6 functions as a co-operative transcriptional activator and that mutations in the protein interaction domain of IRF6 disrupt this activity.
+ Current address: Departments of Microbiology and Molecular Genetics and Pediatrics and Human Development, Michigan State University, East Lansing, MI. USA
# The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors
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