Journal article
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, Vol.18(3), pp.535-545
02/01/2009
DOI: 10.1093/hmg/ddn381
PMCID: PMC2638798
PMID: 19036739
Abstract
Cleft lip and cleft palate (CLP) 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 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 missense 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. Nevertheless, this genotype-phenotype correlation is based on the analysis of structural models rather than on the 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.
Details
- Title: Subtitle
- Missense mutations that cause Van der Woude syndrome and popliteal pterygium syndrome affect the DNA-binding and transcriptional activation functions of IRF6
- Creators
- Hayley J. Little - Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, EnglandNicholas K. Rorick - Univ Iowa, Dept Pediat, Iowa City, IA 52242 USALing-I Su - Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, EnglandClair Baldock - Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, EnglandSaimon Malhotra - Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, EnglandTom Jowitt - Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, EnglandLokesh Gakhar - University of Iowa, Medicine AdministrationRamaswamy Subramanian - Univ Iowa, Dept Biochem, Iowa City, IA 52242 USABrian C. Schutte - University of IowaMichael J. Dixon - University of ManchesterPaul Shore - Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.18(3), pp.535-545
- DOI
- 10.1093/hmg/ddn381
- PMID
- 19036739
- PMCID
- PMC2638798
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- Oxford Univ Press
- Number of pages
- 11
- Grant note
- P50-DE016215; DE13513 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P50DE016215 / NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR) 082868 / Wellcome Trust; European Commission
- Language
- English
- Date published
- 02/01/2009
- Academic Unit
- Medicine Administration
- Record Identifier
- 9984622056702771
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