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

Abstract

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
Volume93
Issue number6
DOIs
Publication statusPublished - Dec 5 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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