Abstract

The goal of Project 0003 is to discover the genes that contribute to isolated cleft lip and palate, a common disorder with complex etiology. This project will study IRF6, a gene that encodes the transcription factor Interferon Regulatory Factor 6. Mutations in IRF6 cause Van der Woude syndrome (VWS). VWS is an outstanding clinical model for isolated cleft lip and palate because the phenotypes of VWS and isolated cleft lip and palate are similar. It is also an outstanding genetic model, since alleles of IRF6 are highly associated with isolated cleft lip and palate in nine geographically distinct populations. These results prove that IRF6 is a key component of a critical pathway in palate development. In this proposal we use mouse models to identify the IRF6 pathway and other genes therein. There are two main hypotheses, 1) IRF6 is a mediator of Tgfb signaling and 2) IRF6 gene targets are essential for palate development. There are three Specific Aims.
Specific Aim 1 will determine which cell-type expresses Irf6 in the palate. This basic information will immediately suggest Irf6 pathways and gene targets.
Specific Aim 2 will determine which pathways require Irf6 for palate development. The Tgfb3 signaling pathway is essential for palate development and Tgfb3 is expressed at about the same time and place as Irf6. Knockout mice will be used to test the hypotheses that Tgfb3 is essential for expression of Irf6 in the palate shelves.
Specific Aim 3 will use microarray analysis to identify the target genes for Irf6 during palate development. In addition, if Irf6 is a mediator for Tgfb3, then gene expression in the palate will be similar in Tgfb3-/- and Irf6-/- mice. Addressing these aims will advance our understanding of Irf6, a gene that is essential in craniofacial development. Further, the IRF6 pathways and targets, discovered in this proposal, will be assessed for their involvement in cleft lip and palate in Project 0001 and in palate development in Project 0004 and Cores 9003 and 9004. This aggregate knowledge will enhance our ability to determine the causes of, and develop preventive interventions for, orofacial clefts.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Specialized Center (P50)
Project #
5P50DE016215-03
Application #
7267094
Study Section
Special Emphasis Panel (ZDE1)
Project Start
Project End
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$186,504
Indirect Cost

  Institution

Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242

  Publications

Howe, Laurence J; Lee, Myoung Keun; Sharp, Gemma C et al. (2018) Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. PLoS Genet 14:e1007501
Bureau, Alexandre; Begum, Ferdouse; Taub, Margaret A et al. (2018) Inferring disease risk genes from sequencing data in multiplex pedigrees through sharing of rare variants. Genet Epidemiol :
Fu, Jack; Beaty, Terri H; Scott, Alan F et al. (2017) Whole exome association of rare deletions in multiplex oral cleft families. Genet Epidemiol 41:61-69
Liu, Dongjing; Wang, Hong; Schwender, Holger et al. (2017) Gene-gene interaction of single nucleotide polymorphisms in 16p13.3 may contribute to the risk of non-syndromic cleft lip with or without cleft palate in Chinese case-parent trios. Am J Med Genet A 173:1489-1494
Wise, Alison S; Shi, Min; Weinberg, Clarice R (2016) Family-Based Multi-SNP X Chromosome Analysis Using Parent Information. Front Genet 7:20
Wise, Alison S; Shi, Min; Weinberg, Clarice R (2015) Learning about the X from our parents. Front Genet 6:15
Li, Qing; Kim, Yoonhee; Suktitipat, Bhoom et al. (2015) Gene-Gene Interaction Among WNT Genes for Oral Cleft in Trios. Genet Epidemiol 39:385-94
Wu, Tao; Schwender, Holger; Ruczinski, Ingo et al. (2014) Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate. PLoS One 9:e88088
Garg, Paras; Ludwig, Kerstin U; Böhmer, Anne C et al. (2014) Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts. Eur J Hum Genet 22:822-30
Baugher, Joseph D; Baugher, Benjamin D; Shirley, Matthew D et al. (2013) Sensitive and specific detection of mosaic chromosomal abnormalities using the Parent-of-Origin-based Detection (POD) method. BMC Genomics 14:367

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