Greig Cephalopolysyndactylie: Analyse einer menschlichen Entwicklungsmutante

人类多指畸形是由肢体发育过程中前后模式的紊乱引起的。我们目前的研究结果表明，不同的人类多指综合征，如Greig综合征- pallister - hall综合征，轴后多指综合征A型和多指综合征IV型是由GLI3基因的点突变引起的。与目前的理论相反，从突变的分布中没有明显的简单的基因型/表型相关性。为了鉴定该蛋白的所有功能重要位点，我们继续鉴定新的GLI3突变。这项研究是由模型生物中自然发生和诱导的Gli突变所描述的表型指导的，特别是小鼠。我们正在建立体外实验来分析特定突变对锌指蛋白保守结构域的假定功能的影响：转录激活和抑制、DNA结合、与微管的粘附、蛋白水解裂解和亚细胞区隔化。此外，我们试图将函数分配到保守域，其作用尚不清楚。通过对与足指畸形相关的人类综合征的分析，对前/后模式这一关键因素的功能表征将有助于理解脊椎动物身体计划中的一般模式程序。

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.