Cranial, facial, and limb malformations constitute a significant proportion of the general incidence of birth defects. They may arise from monogenic, polygenic, and/or multi-factorial processes that result from both cell autonomous and cell non-autonomous mechanisms. The frequent co- existence of craniofacial and limb defects in many inherited malformations likely reflects the shared signaling pathways governing their development. The diagnosis, prevention, and treatment of these processes will first require isolation of a cohort of genes which specify the patterning and cell differentiation of these tissues and then correlation of their altered function with phenotypic consequences. Subsequently, the mechanistic bases of their function must be elucidated with respect to each proteins' structure, interaction with other proteins, and interaction with environmental factors. Ultimately, translating the consequences of mutation to phenotype will lead to new diagnostic paradigms. A central cell autonomous process common to many such malformations is transcriptional regulation of osteoblast differentiation and skeletogenesis. Understanding how the master transcription factor, core binding factor alpha (CBFA1), regulates this process and the biochemical and clinical consequences of mutation in this pathway will lead to a framework for understanding the pathogenesis of other malformations affecting skeletal development as well as for diagnosis subtle defects of the cranium and facies. At the same time, cell non-autonomous processes such as vascular hypoperfusion contribute to the genesis of birth defects including 1imb reduction. One of multiple genetic determinants which contribute to the phenotype is loss of function of endothelial nitric oxide synthase (eNOS). Understanding the gene-gene and gene-environmental interactions which impact this phenotype will lead to a better understanding of how we can prevent the consequences of vascular insufficiency on soft and hard tissue development in utero. These mechanistic studies provide platforms for studying the function of genes which cause other malformation syndromes. One approach to rapidly identify gene genes is to generate a large series of dominant mouse phenotypes by both chromosome-specific and genome-wide ENU mutagenesis followed by comparative genomic and phenotypic analysis with well characterized birth defects registries such as in the Finnish population. The converse strategy is similarly powerful in rapidly identifying the genes defects registries such as in the Finnish population. The converse strategy is similarly powerful in rapidly identifying the gene defects in phenotypically similar malformation syndromes which suggest alteration of similar or identical developmental pathways. This is the case for hydrolethalus and Meckel syndrome, which are characterized by CNS, craniofacial abnormalities, and polydactyly. They have been mapped to human chromosomes 11 and 17, respectively. Comparative genomic and mouse mutagenesis studies in the syntenic regions will expedite the identification of these genes. Together, these studies will identify genes important in pathogenesis of human malformation and elucidate their modes of action in both cell autonomous and cell non-autonomous models mechanisms of development.
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