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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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“[172], aniridia can be caused by point mutation in the conserved SIMO enhancer located 150 kb from PAX6 gene.”
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“The SIMO element regulates the expression of PAX6 in the eye, and we have previously demonstrated that a point mutation in this CRE can cause the congenital eye malformation aniridia by disrupting an autoregulatory PAX6 binding site in the element [14].”
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“and studies in mouse and zebrafish show that the element acts as a strong enhancer in developing ocular structures [97].”
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“As PAX6 itself is a transcription factor and there is an autoregulatory feedback for its expression [Bhatia et al., 2013], the decrease of PAX6 proteins then results in a lower level of mRNA expression.”
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The complexity of epigenetic diseases
Brazel, A. J., & Vernimmen, D. (2015) · The Journal of Pathology · doi:10.1002/path.4647 · Cited by 25
“(B) Reduction of chromosomal looping between the enhancer and the promoter might be due to (1) natural variant or mutation at the enhancer [163], (2) the presence of a new SNP forming a new enhancer/promoter region which titrates the remote enhancer activity [43], or (3) promoter or enhancer hypermethylation [164].”
BackgroundGenome sequencing in families with congenital limb malformations
Elsner, J., Mensah, M. A., Holtgrewe, M., Hertzberg, J., Bigoni, S., Busche, A., Coutelier, M., de Silva, D. C., Elcioglu, N. H., Filges, I., et al. (2021) · Human Genetics · doi:10.1007/s00439-021-02295-y · Cited by 24
Role of Enhancers in Development and Diseases
Maurya, S. S. (2021) · Epigenomes · doi:10.3390/epigenomes5040021 · Cited by 26
Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster
Miguel-Escalada, I., Maestro, M. Á., Balboa, D., Elek, A., Bernal, A., Bernardo, E., Grau, V., García-Hurtado, J., Sebé-Pedrós, A., & Ferrer, J. P. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.07.014 · Cited by 22
Three-dimensional genome: developmental technologies and applications in precision medicine
Li, Y., Tao, T., Du, L., & Zhu, X. M. (2020) · Journal of Human Genetics · doi:10.1038/s10038-020-0737-7 · Cited by 24
“The point mutation of enhancer SIMO in TAD alters the function of the gene PAX6, leading to aniridia (a patient disease) [103].”
BackgroundLong-read genome sequencing identifies cryptic structural variants in congenital aniridia cases
Damián, A., Núñez‐Moreno, G., Jubin, C., Tamayo, A., de Alba, M. R., Villaverde, C., Fund, C., Délepine, M., Leduc, A., Deleuze, J., et al. (2023) · Human Genomics · doi:10.1186/s40246-023-00490-8 · Cited by 24
“Interestingly, HS2 localizes between E180B and SIMO, two well-characterized and highly conserved enhancers for ocular PAX6 expression [4, 31], which have also been previously involved in the etiopathogenesis of aniridia [2, 10, 13].”
BackgroundModeling congenital disease and inborn errors of development inDrosophila melanogaster
Moulton, M. J., & Letsou, A. (2016) · Disease Models & Mechanisms · doi:10.1242/dmm.023564 · Cited by 28
“Moreover, loss of Pax6 or additional components of the eye GRN produces aniridia (iris hypoplasia) not only in flies and humans, but also in zebrafish, frogs, chicks and mice (Bhatia et al., 2013; Kaufman et al., 1995; Nakayama et al., 2015; Takamiya et al., 2015; Treisman, 1999).”
Clinical utility gene card for: Aniridia
Richardson, R., Hingorani, M., van Heyningen, V., Gregory, C. Y., & Moosajee, M. (2016) · European Journal of Human Genetics · doi:10.1038/ejhg.2016.73 · Cited by 24
PAX6 MiniPromoters drive restricted expression from rAAV in the adult mouse retina
Hickmott, J. W., Chen, C., Arenillas, D. J., Korecki, A. J., Lam, S. L., Molday, L. L., Bonaguro, R. J., Zhou, M., Chou, A., Mathelier, A., et al. (2016) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2016.51 · Cited by 23
Souzeau, E., Rudkin, A. K., Dubowsky, A., Casson, R. J., Muecke, J. S., Mancel, E., Whiting, M., Mills, R. A., Burdon, K. P., & Craig, J. E. (2018) · Europe PMC (PubMed Central) · Cited by 23
McCole, R. B., Fonseka, C. Y., Koren, A., & Wu, C.-T. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004646 · Cited by 23
“endogenously as enhancers [4,17–24].”
Highlighting transcribed ultraconserved regions in human diseases
Zambalde, É. P., Mathias, C., Rodrigues, A. C., Ribeiro, E. M. D. S. F., Gradia, D. F., Călin, G. A., & de Oliveira, J. C. (2019) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1567 · Cited by 23
“This mutation results in the deregulation of the gene, and may be associated with development defect (Bhatia et al., 2013).”
BackgroundThe Genetic Determinants of Axial Length: From Microphthalmia to High Myopia in Childhood
Jackson, D. J., & Moosajee, M. (2023) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-102722-090617 · Cited by 22
“Mutations affecting PAX6 enhancers can also cause aniridia (5).”
BackgroundReis, L. M., Seese, S. E., Costakos, D. M., & Semina, E. V. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2024.101288 · Cited by 22
Dynamic patterning by morphogens illuminated by cis-regulatory studies
Irizarry, J., & Stathopoulos, A. (2021) · Development · doi:10.1242/dev.196113 · Cited by 19
“Enhancer activity is context dependent and perturbing its action can lead to developmental defects and disease (Bhatia et al., 2013; Lupiáñez et al., 2015; Uslu et al., 2014).”
BackgroundMutation spectrum of PAX6 and clinical findings in 95 Chinese patients with aniridia.
You, B., Zhang, X., Xu, K. Y., Xie, Y., Ye, H., & Li, Y. (2020) · PubMed Central · Cited by 20
Quantitative spatial and temporal assessment of regulatory element activity in zebrafish
Bhatia, S., Kleinjan, D. J., Uttley, K., Mann, A., Dellepiane, N., & Bickmore, W. A. (2021) · eLife · doi:10.7554/elife.65601 · Cited by 17
“The activities of a large number of putative human and mouse CREs have been assessed in transgenic zebrafish models, irrespective of the primary sequence conservation of the mammalian CREs in zebrafish (Bhatia et al., 2013; Bhatia et al., 2015; Chahal et al., 2019; Goode and Elgar, 2013; Rainger et al., 2014; Ravi et…”
BackgroundSelf-citationGenetics and epidemiology of aniridia: Updated guidelines for genetic study
Blanco‐Kelly, F., Tarilonte, M., Villamar, M., Damián, A., Tamayo, A., Moreno-Pelayo, M. Á., Ayuso, C., & Cortón, M. (2021) · Archivos de la Sociedad Española de Oftalmología (English Edition) · doi:10.1016/j.oftale.2021.02.002 · Cited by 18
“19, 2018 29 (18) Australasia and Southeast Asia Aniridia Sanger + MLPA 95% WAGR/O Plaisancié et al.”
BackgroundExpanded Insights Into Mechanisms of Gene Expression and Disease Related Disruptions
Smith, M., & Flodman, P. L. (2018) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2018.00101 · Cited by 18
“Bhatia et al. (2013) reported results of studies in cases of aniridia with intact PAX6 protein coding sequence but with disruption of an ultra-conserved cis-regulatory element located 150 kb downstream from PAX6.”
ResultLópez-Soriano, V., Rey, A. D., Mukherjee, R., Inglehearn, C. F., Coppieters, F., Bauwens, M., Willaert, A., & Baere, E. B. W. D. (2024) · Nature Communications · doi:10.1038/s41467-024-45381-1 · Cited by 19
“Finally, to identify overrepresented Gene Ontology (GO) terms andinferpossibleenrichedpathwaysamongthepotentialtargetgenes under UCNE regulation, GO enrichment analyses were performed using Enrichr 89 .”
BackgroundMethodDeep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants
McDonnell, A. F., Plech, M., Livesey, B. J., Gerasimavicius, L., Owen, L. J., Hall, H. N., FitzPatrick, D. R., Marsh, J. A., & Kudla, G. (2024) · Molecular Systems Biology · doi:10.1038/s44320-024-00043-8 · Cited by 16
“…cell self-renewal and differentiation (Terzic and Saraga-Babic, 1999; Sun et al, 2015; Sansom et al, 2009; Thakurela et al, 2016; Aota et al, 2003; Bhatia et al, 2013; Inoue et al, 2007; Hayashi et al, 1987; Narasimhan et al, 2015; Epstein et al, 1994; Xu et al, 1999; Coutinho et al, 2011).”
Functional characteristics of novel pancreatic Pax6 regulatory elements
Buckle, A., Nozawa, R.-S., Kleinjan, D., & Gilbert, N. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy255 · Cited by 17
“Results 85 Identification of novel human and mouse conserved pancreatic regulatory elements 86 In contrast to the downstream region of PAX6, which has a significant role in disease aetiology of aniridia 87 patients, the upstream region towards RCN1 is less well studied; it only includes the E-200 element and E88 55 cl…”
BackgroundSelf-citationNovel Intragenic PAX6 Deletion in a Pedigree with Aniridia, Morbid Obesity, and Diabetes
Boese, E. A., Tollefson, M. R., Schnieders, M. J., Darbro, B. W., Alward, W. L. M., & Fingert, J. H. (2019) · Current Eye Research · doi:10.1080/02713683.2019.1649704 · Cited by 18
Green, D. J., Lenassi, E., Manning, C. S., McGaughey, D. M., Sharma, V., Black, G. C. M., Ellingford, J. M., & Sergouniotis, P. I. (2021) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.62.7.16 · Cited by 18
BAT Hi-C maps global chromatin interactions in an efficient and economical way
Huang, J. S., Jiang, Y., Zheng, H., & Ji, X. (2019) · Methods · doi:10.1016/j.ymeth.2019.08.004 · Cited by 16
Gene Dosage Sensitivity and Human Genetic Diseases
Veitia, R. A., Zschocke, J., & Birchler, J. A. (2025) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.70058 · Cited by 14
“A notable example is observed with heterozygous loss of PAX6 , leading to aniridia [34], which illustrates how a threshold effect can convert a 50% difference in gene dosage into a nearly 100% difference in protein dosage [35].”
InfluentialDisruption of regulatory domains and novel transcripts as disease‐causing mechanisms
Allou, L., & Mundlos, S. (2023) · BioEssays · doi:10.1002/bies.202300010 · Cited by 15
“SVs that occur within TADs and affect CREs can result in a tissue-specific loss of function or gain of function of their endogenous target genes, which can be located several hundred kilobases away [77–84] (Figure 3A–”
BackgroundCassinari, K., Rovelet‐Lecrux, A., Tury, S., Quenez, O., Richard, A., Charbonnier, C., Olaso, R., Boland, A., Deleuze, J., Besancenot, J.-F., et al. (2020) · Movement Disorders · doi:10.1002/mds.28090 · Cited by 15
Recommendations for clinical interpretation of variants found in non-coding regions of the genomePreprint
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. (2021) · medRxiv · doi:10.1101/2021.12.28.21267792 · Cited by 15
Diagnostic yield of targeted next-generation sequencing in infantile nystagmus syndrome
Choi, J., Kim, S. J., Thomas, M. G., Jung, J. H., Oh, E. H., Shin, J., Cho, J. W., Kim, H.-S., Park, J., Choi, S., et al. (2021) · Ophthalmic Genetics · doi:10.1080/13816810.2021.1938138 · Cited by 14
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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