The goal of this program project grant application is to understand the molecular basis of vel-cardio-facial syndrome (VCFS). This human syndrome has an incidence that is greater that 1 in 5, 000 live births and is characterized by defects involving several organ and tissue systems. The children have cleft palate, pharyngeal insufficiency, cardiac and conotruncal anomalies, immunological abnormalities that result from thymic aplasia and by hypoparathyroidism. As the children grow, they exhibit learning disabilities and older individuals develop psychiatric illness. Because several of the affected organs are derived from neural crest and from the pharyngeal pouches, it was postulated that at least some of the phenotypes are the result of a developmental field defect. A large proportion of VCFS patients have interstitial deletion of chromosome 22 suggesting that haploinsufficiency of genes in the deleted region causes the disorder. To understand the molecular basis of this disorder, we constructed a high resolution physical map of the 22q11 region in the form of overlapping yeast artificial chromosomes and bacterial clones, mapped highly polymorphic markers and used them to define a commonly deleted region. We also identified several genes and isolated cDNA fragments corresponding to genes present in this region. We now propose to conduct a series of experiments to define the basis for VCGS. In Project 1, we will further define the commonly deleted region by examining new VCFS patients a and making somatic cell hybrids which would allow the separation of the deleted chromosome from the normal counterpart. In this project, we also propose to define the breakpoints of deletions and obtain full length cDNAs corresponding to the short fragments. Because the gene(s) involved in VCFS should be expressed during neural crest migration, in Project 2 we propose to examine the developmental patterns of expression of the genes isolated in Project 1. RNA from human fetal tissues and different stages of mouse development together with in situ hybridization will be used to identify genes that have the appropriate developmental profile and therefore are candidate genes for VCFS. In Project 3, we plan to develop mouse models for VCGS by generating mice by targeted inactivation of specific candidate genes as well as deletions corresponding to the commonly deleted region in human patients. These projects will be supported by an administrative and cell/molecular biology core.
| Kong, Ping; Racedo, Silvia E; Macchiarulo, Stephania et al. (2014) Tbx1 is required autonomously for cell survival and fate in the pharyngeal core mesoderm to form the muscles of mastication. Hum Mol Genet 23:4215-31 |
| Herman, Sean B; Guo, Tingwei; McGinn, Donna M McDonald et al. (2012) Overt cleft palate phenotype and TBX1 genotype correlations in velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients. Am J Med Genet A 158A:2781-7 |
| John, Anitha S; McDonald-McGinn, Donna M; Zackai, Elaine H et al. (2009) Aortic root dilation in patients with 22q11.2 deletion syndrome. Am J Med Genet A 149A:939-42 |
| Burdick, Katherine E; Funke, Birgit; Goldberg, Joseph F et al. (2007) COMT genotype increases risk for bipolar I disorder and influences neurocognitive performance. Bipolar Disord 9:370-6 |
| Funke, Birgit H; Lencz, Todd; Finn, Christine T et al. (2007) Analysis of TBX1 variation in patients with psychotic and affective disorders. Mol Med 13:407-14 |
| DeRosse, Pamela; Funke, Birgit; Burdick, Katherine E et al. (2006) COMT genotype and manic symptoms in schizophrenia. Schizophr Res 87:28-31 |
| Chegar, Burke E; Tatum 3rd, Sherard A; Marrinan, Eileen et al. (2006) Upper airway asymmetry in velo-cardio-facial syndrome. Int J Pediatr Otorhinolaryngol 70:1375-81 |
| Burdick, Katherine E; Lencz, Todd; Funke, Birgit et al. (2006) Genetic variation in DTNBP1 influences general cognitive ability. Hum Mol Genet 15:1563-8 |
| Long, Jeffrey M; LaPorte, Patricia; Merscher, Sandra et al. (2006) Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome. Neurogenetics 7:247-57 |
| DeRosse, Pamela; Funke, Birgit; Burdick, Katherine E et al. (2006) Dysbindin genotype and negative symptoms in schizophrenia. Am J Psychiatry 163:532-4 |
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