ZFIN ID: ZDB-PUB-200303-1
Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia
Bhatia, S., Bengani, H., Fish, M., Brown, A., Divizia, M.T., de Marco, R., Damante, G., Grainger, R., van Heyningen, V., Kleinjan, D.A.
Date: 2013
Source: American journal of human genetics   93: 1126-34 (Review)
Registered Authors: Bhatia, Shipra, Brownlie, Alison J., van Heyningen, Veronica
Keywords: none
MeSH Terms:
  • Animals
  • Aniridia/diagnosis
  • Aniridia/genetics*
  • Aniridia/metabolism*
  • Base Sequence
  • Enhancer Elements, Genetic*
  • Eye/pathology
  • Eye Proteins/genetics*
  • Gene Expression Regulation, Developmental
  • Gene Order
  • Homeodomain Proteins/genetics*
  • Homeostasis/genetics*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors/genetics*
  • Phenotype
  • Repressor Proteins/genetics*
  • Sequence Alignment
  • Zebrafish
PubMed: 24290376 Full text @ Am. J. Hum. Genet.
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.