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Disruption of Autoregulatory Feedback by a Mutation in a Remote, Ultraconserved PAX6 Enhancer Causes Aniridia
Open accessAbstract
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.
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“In humans, a point mutation within a downstream enhancer controlling PAX6 expression causes the congenital eye malformation aniridia [196].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [196]
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“This mutation was found to prevent PAX6 itself from binding to the enhancer [196].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [196]
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Collobert, M., Bocher, O., Nabec, A. L., Génin, E., Férec, C., & Moisan, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052599 · Cited by 13
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Metadata
- 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.
- Affiliations
- Institute of Genetics and Cancer (GB)
- University of Virginia (US)
- Istituto Giannina Gaslini (IT)
- Corresponding author
- van Heyningen, Veronica
- Kleinjan, Dirk A.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 93
- Issue
- 6
- Pages
- 1126-1134
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3852925
- OpenAlex
- W2055426186
- Cited by
- 196
- References
- 39
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 16 · 2023: 20 · 2022: 18 · 2021: 24 · 2020: 16 · 2019: 16 · 2018: 19 · 2017: 8 · 2016: 21 · 2015: 11 · 2014: 6
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System (University of Udine) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Eye Institute (R01EY022954, R01EY018000)
- Topics
- Health Sciences › Medicine › Ophthalmology › Ocular Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Pax6, aniridia, ultraconserved elements, cis-regulatory elements, enhancers, autoregulatory loop, haploinsufficiency, de novo mutations, eye development, congenital eye malformation
- MeSH terms
- PAX6 Transcription Factor, Animals, Base Sequence, Enhancer Elements, Genetic, Eye, Eye Proteins, Homeostasis, Humans, Molecular Sequence Data, Mutation, Phenotype, Repressor Proteins, Zebrafish, Aniridia, Sequence Alignment, Homeodomain Proteins, Gene Expression Regulation, Developmental, Gene Order, Mice, Paired Box Transcription Factors
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