The goal of this study is to develop animal models of Velocardiofacial Syndrome (VCFS) that will allow comprehensive assessment of craniofacial development both prenatally and post-natally, and that will provide a system for identifying the genes responsible for known anomalies of this syndrome. Haplo-insufficiency for a minimal critical region of Chr22 is strongly correlated with the occurrence of cleft lip and palate. We have mapped and are currently sequencing 1.5 MB of mouse Chr 16 that is homologous to human Chr 22 in collaboration with Dr. Bruce Roe, University of Oklahoma. These studies provide the information necessary to develop targeted deletions in embryonic stem cells to develop a VCFS model. In the first step, targeted homologous recombination has been used to delete the Gsc1 gene to permit assessment of its possible contribution to craniofacial disorders. (Disruption of the closely related gene, Gsc, results in craniofacial anomalies). PAC transgenic mice will be tested for complementation of defects seen in knock-out mice, localizing the region containing the relevant gene(s). Candidate genes from the deleted region identified from our independent sequencing project, or genes that may be affected downstream by the deletion will further elucidate gene function in this region. Specifically, our goals are to: 1. Create haplo-insufficiency in mice analogous to that in humans with Velocardiofacial Syndrome. 2. Assess VCFS-related phenotypes of heart and cranio-facial development in mice that are nullisomic (if viable), monosomic or trisomic for the affected region. 3. Analyze gene expression in aneuploid mice. Expression of individually targeted genes will be assessed directly by RT-PCR, Northern and (where applicable) Western blotting, and by in situ hybridization. To study the larger changes expression patterns, large cDNA arrays will be hybridized with RNA from corresponding tissues of control and engineered mice. 4. Identify by positional and functional cloning the genes responsible for VCFS-related phenotypes. We will complement deletion phenotypes with BAC/PAC transgenesis as a first step in positional cloning of genes responsible for the phenotypes. We will also mate deleted mice to ENU- treated males to uncover recessive mutations in genes from the VCFS region.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Program Projects (P01)
Project #
2P01DC002027-06A1
Application #
6321355
Study Section
Communication Disorders Review Committee (CDRC)
Project Start
1994-04-01
Project End
2004-01-31
Budget Start
Budget End
Support Year
6
Fiscal Year
2000
Total Cost
$211,315
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Belangero, Sintia Iole Nogueira; Bellucco, Fernanda Teixeira da Silva; Cernach, Mirlene C S P et al. (2009) Interrupted aortic arch type B in A patient with cat eye syndrome. Arq Bras Cardiol 92:e29-31, e56-8
Goldmuntz, Elizabeth; Driscoll, Deborah A; Emanuel, Beverly S et al. (2009) Evaluation of potential modifiers of the cardiac phenotype in the 22q11.2 deletion syndrome. Birth Defects Res A Clin Mol Teratol 85:125-9
Bearden, Carrie E; van Erp, Theo G M; Dutton, Rebecca A et al. (2009) Alterations in midline cortical thickness and gyrification patterns mapped in children with 22q11.2 deletions. Cereb Cortex 19:115-26
Nogueira, Sintia Iole; Hacker, April M; Bellucco, Fernanda T S et al. (2008) Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum. Eur J Med Genet 51:226-30
Nogueira, Sintia Iole; Hacker, April M; Bellucco, Fernanda T S et al. (2007) Deletion 22q11.2: report of a complex meiotic mechanism of origin. Am J Med Genet A 143A:1778-81
Ruotolo, Rachel A; Veitia, Nestor A; Corbin, Aaron et al. (2006) Velopharyngeal anatomy in 22q11.2 deletion syndrome: a three-dimensional cephalometric analysis. Cleft Palate Craniofac J 43:446-56
Vorstman, J A S; Jalali, G R; Rappaport, E F et al. (2006) MLPA: a rapid, reliable, and sensitive method for detection and analysis of abnormalities of 22q. Hum Mutat 27:814-21
Kato, Takema; Inagaki, Hidehito; Yamada, Kouji et al. (2006) Genetic variation affects de novo translocation frequency. Science 311:971
Driscoll, Deborah A; Boland, Torrey; Emanuel, Beverly S et al. (2006) Evaluation of potential modifiers of the palatal phenotype in the 22q11.2 deletion syndrome. Cleft Palate Craniofac J 43:435-41
McDonald-McGinn, Donna M; Minugh-Purvis, Nancy; Kirschner, Richard E et al. (2005) The 22q11.2 deletion in African-American patients: an underdiagnosed population? Am J Med Genet A 134:242-6

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