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Hum Genet. 2018 Oct;137(10):831-846. doi: 10.1007/s00439-018-1940-x. Epub 2018 Oct 5.

Implication of non-coding PAX6 mutations in aniridia.

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Service de Génétique Médicale, Pavillon Lefebvre, Hôpital Purpan, CHU Toulouse, Place du Dr Baylac, 31059, Toulouse Cedex 9, France.
INSERM U1056, Université Toulouse III, Toulouse, France.
Department of Genetics, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.
Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
Service de Génétique Médicale, Pavillon Lefebvre, Hôpital Purpan, CHU Toulouse, Place du Dr Baylac, 31059, Toulouse Cedex 9, France.
Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Filière SENSGENE, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Laboratoire de Génétique Ophtalmologique INSERM U1163, Institut Imagine, Paris, France.
Service de Génétique Médicale, CHU Estaing, Clermont-Ferrand, France.
Service de Génétique, CHU de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France.
Department of Genetics, Hospital of Cáceres, Cáceres, Spain.
INSERM U1056, Université Toulouse III, Toulouse, France.


There is an increasing implication of non-coding regions in pathological processes of genetic origin. This is partly due to the emergence of sophisticated techniques that have transformed research into gene expression by allowing a more global understanding of the genome, both at the genomic, epigenomic and chromatin levels. Here, we implemented the analysis of PAX6, whose coding loss-of-function variants are mainly implied in aniridia, by studying its non-coding regions (untranslated regions, introns and cis-regulatory sequences). In particular, we have taken advantage of the development of high-throughput approaches to screen the upstream and downstream regulatory regions of PAX6 in 47 aniridia patients without identified mutation in the coding sequence. This was made possible through the use of custom targeted resequencing and/or CGH array to analyze the entire PAX6 locus on 11p13. We found candidate variants in 30 of the 47 patients. 9/30 correspond to the well-known described 3' deletions encompassing SIMO and other enhancer elements. In addition, we identified numerous different variants in various non-coding regions, in particular untranslated regions. Among these latter, most of them demonstrated an in vitro functional effect using a minigene strategy, and 12/21 are thus considered as causative mutations or very likely to explain the phenotypes. This new analysis strategy brings molecular diagnosis to more than 90% of our aniridia patients. This study revealed an outstanding mutation pattern in non-coding PAX6 regions confirming that PAX6 remains the major gene for aniridia.


5′UTR; Aniridia; Cis-regulatory region; Eye development; Minigene assay; Non-coding mutation; PAX6

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