The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
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 the citing paper
“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]
In the citing paper
“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]
Citations
Cites
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Simple and highly efficient BAC recombineering using galK selection
Warming, S. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni035 · Cited by 1,216
Mouse Small eye results from mutations in a paired-like homeobox-containing gene
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Highly Conserved Non-Coding Sequences Are Associated with Vertebrate Development
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Phenotypic robustness conferred by apparently redundant transcriptional enhancers
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Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence
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Self-citationShadow Enhancers Foster Robustness of Drosophila Gastrulation
Perry, M. W., Boettiger, A. N., Bothma, J. P., & Levine, M. (2010) · Current Biology · doi:10.1016/j.cub.2010.07.043 · Cited by 396
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Deletion of Ultraconserved Elements Yields Viable Mice
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Cited by
Sorted by citations
Long-range enhancer–promoter contacts in gene expression control
Schoenfelder, S., & Fraser, P. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0128-0 · Cited by 1,102
Structural variation in the 3D genome
Spielmann, M., Lupiáñez, D. G., & Mundlos, S. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0007-0 · Cited by 752
De novo mutations in regulatory elements in neurodevelopmental disorders
Short, P. J., McRae, J. F., Gallone, G., Sifrim, A., Won, H., Geschwind, D. H., Wright, C. F., Firth, H. V., FitzPatrick, D. R., Barrett, J. C., et al. (2018) · Nature · doi:10.1038/nature25983 · Cited by 274
Recommendations for clinical interpretation of variants found in non-coding regions of the genome
Ellingford, J. M., Ahn, J. W., Bagnall, R. D., Baralle, D., Barton, S., Campbell, C., Downes, K., Ellard, S., Duff‐Farrier, C. R. A., FitzPatrick, D. R., et al. (2022) · Genome Medicine · doi:10.1186/s13073-022-01073-3 · Cited by 274
“Functional experiments show that deletion of the element disrupts maintenance of PAX6 expression [82].”
BackgroundHuman Structural Variation: Mechanisms of Chromosome Rearrangements
Weckselblatt, B., & Rudd, M. K. (2015) · Trends in Genetics · doi:10.1016/j.tig.2015.05.010 · Cited by 261
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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