Maas Sarah A, Fallon John F
Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53706, USA.
Dev Dyn. 2005 Feb;232(2):345-8. doi: 10.1002/dvdy.20254.
In most instances of preaxial polydactyly (PPD), Sonic Hedgehog (Shh), an essential limb patterning signal, is ectopically expressed in an anterior region of the developing limb in addition to the normal posterior domain. It is thought that this anterior Shh expression leads directly to the development of the extra digits. Recent reports have identified a conserved limb-specific Shh enhancer approximately 1 megabase upstream of the Shh transcription initiation site, and individual base pair changes within this region are associated with PPD. We report here that a single base pair change within this enhancer is sufficient to drive beta-galactosidase expression in both anterior and posterior limb domains, similar to Shh expression in animal PPD models, whereas a wild-type construct is expressed only in the posterior limb, similar to Shh expression in normal embryos. These findings provide the first direct evidence that a single base pair change within the limb-specific Shh enhancer acts as a genetic basis for PPD.
在大多数轴前多指（PPD）病例中，音猬因子（Shh）作为一种重要的肢体模式形成信号，除了在发育中肢体的正常后部区域表达外，还在其前部区域异位表达。据认为，这种前部Shh表达直接导致额外手指的发育。最近的报告在Shh转录起始位点上游约1兆碱基处鉴定出一个保守的肢体特异性Shh增强子，该区域内的单个碱基对变化与PPD相关。我们在此报告，该增强子内的单个碱基对变化足以驱动β-半乳糖苷酶在前部和后部肢体区域表达，类似于动物PPD模型中的Shh表达，而野生型构建体仅在后肢表达,类似于正常胚胎中的Shh表达。这些发现提供了首个直接证据，表明肢体特异性Shh增强子内的单个碱基对变化是PPD的遗传基础。
