Greig Cephalopolysyndactylie: Analyse einer menschlichen Entwicklungsmutante

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Polydactylies in man are caused by disturbances of anterior/ posterior patterning during limb development. Our present results indicate that different human polydactyly syndromes such as Greig syndrome-Pallister-Hall Syndrome, Postaxial Polydactyly Type A and Polydyctyly Type IV are caused by point mutations in the GLI3 gene. Contrary to a current theory, no simple genotype/phenotype correlation is evident from the distribution of mutations. To identify all functionally important sites of the protein, we continue to identify novel GLI3 mutations. This search is guided by the phenotypes described for both naturally occurring and induced Gli mutations in model organisms, in particular the mouse. We are setting up in vitro assays to analyze the consequences of specific mutations on the presumptive functions of conserved domains of this zinc finger protein: transcriptional activation and repression, DNA binding, adhesion to the microtubules, proteolytic cleavage and subcellular compartimentalization. In addition we try to assign functions to conserved domains the role of which is unknown, as yet. The functional characterization of this key factor of anterior/posterior patterning, directed by the analysis of human syndromes associated with poydactyly, will contribute to the understanding of general patterning procedures within the vertebrate body plan.