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

Shipra Bhatia, Hemant Bengani, Margaret Fish, Alison Brown, Maria Teresa Divizia, Riccardo de Marco, Guiseppe Damante, Robert Grainger, Veronica van Heyningen, Dirk A Kleinjan

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)1126-1134
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number6
Early online date23 Nov 2013
Publication statusPublished - 5 Dec 2013


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