Missense Mutations That Cause Van Der Woude Syndrome and Popliteal Pterygium Syndrome Affect the DNA-Binding and Transcriptional Activation Functions of IRF6
Human Molecular Genetics, 2009, Vol. 18, No. 3 535–545 doi:10.1093/hmg/ddn381 Advance Access published on November 26, 2008 Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6 Hayley J. Little1,2,{, Nicholas K. Rorick3,{, Ling-I Su1,{, Clair Baldock1, Saimon Malhotra1, Tom Jowitt1, Lokesh Gakhar4, Ramaswamy Subramanian4, Brian C. Schutte3,{, Michael J. Dixon1,2,Ã and Paul Shore1 1Faculty of Life Sciences, Michael Smith Building and 2Dental School, University of Manchester, Oxford Road, Manchester M13 9PT, UK, 3Department of Pediatrics and Interdisciplinary PhD Program in Genetics and 4Department of Biochemistry, University of Iowa, Iowa City, IA, USA Received September 26, 2008; Revised and Accepted November 10, 2008 Cleft lip and cleft palate (CLP) are common disorders that occur either as part of a syndrome, where struc- tures other than the lip and palate are affected, or in the absence of other anomalies. Van der Woude syn- drome (VWS) and popliteal pterygium syndrome (PPS) are autosomal dominant disorders characterized by combinations of cleft lip, CLP, 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 nonsense 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.
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