title: Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia.
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.
authors.affiliation: MRC Human Genetics Unit at the MRC IGMM at the University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Shipra
authors.initials: S
authors.lastname: Bhatia
authors.forename: Hemant
authors.initials: H
authors.lastname: Bengani
authors.forename: Margaret
authors.initials: M
authors.lastname: Fish
authors.forename: Alison
authors.initials: A
authors.lastname: Brown
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Divizia
authors.forename: Riccardo
authors.initials: R
authors.lastname: de Marco
authors.forename: Guiseppe
authors.initials: G
authors.lastname: Damante
authors.forename: Robert
authors.initials: R
authors.lastname: Grainger
authors.forename: Veronica
authors.initials: V
authors.lastname: van Heyningen
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Kleinjan
mesh_terms: D000818:Animals; D015783:Aniridia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D004742:Enhancer Elements, Genetic; D005123:Eye / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D023061:Gene Order; D018398:Homeodomain Proteins / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*; D016415:Sequence Alignment; D015027:Zebrafish
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins