PUBLICATION
Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia
- Authors
- Bhatia, S., Bengani, H., Fish, M., Brown, A., Divizia, M.T., de Marco, R., Damante, G., Grainger, R., van Heyningen, V., Kleinjan, D.A.
- ID
- ZDB-PUB-200303-1
- Date
- 2013
- Source
- American journal of human genetics 93: 1126-34 (Review)
- Registered Authors
- Bhatia, Shipra, 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.
Citation
Bhatia, S., Bengani, H., Fish, M., Brown, A., Divizia, M.T., de Marco, R., Damante, G., Grainger, R., van Heyningen, V., Kleinjan, D.A. (2013) Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia. American journal of human genetics. 93:1126-34.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping