Abstract

Cleft lip and palate (CL/P) is a major congenital structural anomaly that is notable for significant lifelong morbidity and complex etiology. The extensive psychological, surgical, speech and dental involvement emphasize the importance of understanding the underlying causes. Cleft lip and palate, like other complex diseases, provides a challenge in determining the multiple genetic, stochastic, and environmental factors that lead to its phenotype. In this proposal, the P.I. will pursue the complex causes of cleft lip and palate through investigations of a genetic form of clefting, Van der Woude syndrome (VDWS). VDWS is an excellent model of the more than 300 syndromic forms of CL/P. VDWS is the most prevalent syndromic form of CL/P and its clinical presentation is most similar to nonsyndromic classes. The main goal of this proposal is to discover the structure and function of the VDWS gene. A more long-term goal is to identify gene-gene and gene-environment interactions. These goals will be achieved with the following experiments: 1) Identification of the VDWS gene. A Taqman assay will be used to screen for disease-causing microdeletions that may further restrict the region that contains the VDWS gene. Gene-finding techniques, including the sequence analysis of the entire 600 kb critical region, will be used to identify transcriptional units. Mutation screens will be used to find disease-causing changes in the DNA. 2) Characterization of the VDWS gene and its mouse homologue, including complete cDNA and genomic sequence analysis, the study of temporal and tissue-specific expression to identify developmental pathways that require the VDWS gene function and screens for gene homologues which may function in the same pathway 3) identification of sequences that regulate VDWS gene expression and the development of transgenic mouse models, including a mouse knockout that will be used in 4) long-term studies that will include complementation experiments to identify other genes in the pathway and investigate the effects of environmental factors on the VDWS gene.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013513-02
Application #
6379968
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Small, Rochelle K
Project Start
2000-09-01
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$285,807
Indirect Cost

  Institution

Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242

  Publications

Kousa, Youssef A; Moussa, Dina; Schutte, Brian C (2017) IRF6 expression in basal epithelium partially rescues Irf6 knockout mice. Dev Dyn 246:670-681
Smith, Arianna L; Kousa, Youssef A; Kinoshita, Akira et al. (2017) Generation and characterization of a conditional allele of Interferon Regulatory Factor 6. Genesis 55:
Kousa, Y A; Roushangar, R; Patel, N et al. (2017) IRF6 and SPRY4 Signaling Interact in Periderm Development. J Dent Res 96:1306-1313
Kousa, Youssef A; Schutte, Brian C (2016) Toward an orofacial gene regulatory network. Dev Dyn 245:220-32
Fakhouri, Walid D; Rahimov, Fedik; Attanasio, Catia et al. (2014) An etiologic regulatory mutation in IRF6 with loss- and gain-of-function effects. Hum Mol Genet 23:2711-20
Peyrard-Janvid, Myriam; Leslie, Elizabeth J; Kousa, Youssef A et al. (2014) Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. Am J Hum Genet 94:23-32
Aldhamen, Y A; Seregin, S S; Kousa, Y A et al. (2013) Improved cytotoxic T-lymphocyte immune responses to a tumor antigen by vaccines co-expressing the SLAM-associated adaptor EAT-2. Cancer Gene Ther 20:564-75
de la Garza, Gabriel; Schleiffarth, Jack Robert; Dunnwald, Martine et al. (2013) Interferon regulatory factor 6 promotes differentiation of the periderm by activating expression of Grainyhead-like 3. J Invest Dermatol 133:68-77
Leslie, Elizabeth J; Standley, Jennifer; Compton, John et al. (2013) Comparative analysis of IRF6 variants in families with Van der Woude syndrome and popliteal pterygium syndrome using public whole-exome databases. Genet Med 15:338-44
Leslie, Elizabeth J; Mancuso, Jennifer L; Schutte, Brian C et al. (2013) Search for genetic modifiers of IRF6 and genotype-phenotype correlations in Van der Woude and popliteal pterygium syndromes. Am J Med Genet A 161A:2535-2544

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