Disruption of Autoregulatory Feedback by a Mutation in a Remote, Ultraconserved PAX6 Enhancer Causes Aniridia

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• 作者：Shipra Bhatia ; Hemant Bengani ; Margaret Fish ; Alison Brown ; Maria聽Teresa Divizia ; Riccardo de聽Marco ; Guiseppe Damante ; Robert Grainger ; Veronica van聽Heyningen ; Dirk聽A. Kleinjan
• 刊名：The American Journal of Human Genetics
• 出版年：5 December, 2013
• 年：2013
• 卷：93
• 期：6
• 页码：1126-1134
• 全文大小：2424 K

文摘

The strictly regulated expression of most pleiotropic developmental control genes is critically dependent on the activity of long-range cis-regulatory elements. This was revealed by the identification of individuals with a genetic condition lacking coding-region mutations in the gene commonly associated with the disease but having a variety of nearby chromosomal abnormalities, collectively described as cis-ruption disease cases. The congenital eye malformation aniridia is caused by haploinsufficiency of the developmental regulator PAX6. We discovered a de novo point mutation in an ultraconserved cis-element located 150 kb downstream from PAX6 in an affected individual with intact coding region and chromosomal locus. The element SIMO acts as a strong enhancer in developing ocular structures. The mutation disrupts an autoregulatory PAX6 binding site, causing loss of enhancer activity, resulting in defective maintenance of PAX6 expression. These findings reveal a distinct regulatory mechanism for genetic disease by disruption of an autoregulatory feedback loop critical for maintenance of gene expression through development.