Greig Cephalopolysyndactylie: Analyse einer menschlichen Entwicklungsmutante

Greig 头多指并指：人类发育突变体的分析

• 批准号: 5229196
• 负责人: Professor Dr. Karl-Heinz Grzeschik
• 金额: --
• 依托单位: Zentrum für Humangenetik
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 1995
• 资助国家: 德国
• 起止时间: 1994-12-31 至 2001-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5229196?language=en
• 关键词: Greig; Cephalopolysyndactylie; Analyse; einer; menschlichen

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.

人类的多指畸形是由肢体发育过程中的前/后模式紊乱引起的。我们目前的研究结果表明，不同的人类多指（趾）综合征，如格雷格综合征-帕利斯特-霍尔综合征，轴后多指（趾）A型和多指（趾）IV型是由GLI 3基因的点突变引起的。与目前的理论相反，从突变的分布来看，没有简单的基因型/表型相关性是明显的。为了鉴定蛋白质的所有功能重要位点，我们继续鉴定新的GLI 3突变。该搜索由模型生物体（特别是小鼠）中天然发生的和诱导的Gli突变所描述的表型指导。我们正在建立体外试验，以分析特定突变对这种锌指蛋白保守结构域的推定功能的后果：转录激活和抑制，DNA结合，粘附到微管，蛋白水解裂解和亚细胞compartimentalization。此外，我们试图分配功能的保守域的作用是未知的，至今。前/后图案的这一关键因素的功能表征，指导分析人类综合征相关的缺指，将有助于了解一般图案程序内的脊椎动物身体计划。