Congenital microcoria deletion in mouse links Sox21 dysregulation to disease and suggests a role for TGFB2 in glaucoma and myopia

Elisa Erjavec; Clémentine Angée; Djihad Hadjadj; Bruno Passet; Pierre David; Corinne Kostic; Emmanuel Dodé; Xavier Zanlonghi; Nicolas Cagnard; Brigitte Nedelec; Sylvain V Crippa; Christine Bole-Feysot; Mohammed Zarhrate; Sophie Creuzet; Johan Castille; Jean-Luc Vilotte; Patrick Calvas; Julie Plaisancié; Nicolas Chassaing; Josseline Kaplan; Jean-Michel Rozet; Lucas Fares Taie

doi:10.1016/j.ajhg.2024.08.019

Congenital microcoria deletion in mouse links Sox21 dysregulation to disease and suggests a role for TGFB2 in glaucoma and myopia

Am J Hum Genet. 2024 Sep 13:S0002-9297(24)00305-7. doi: 10.1016/j.ajhg.2024.08.019. Online ahead of print.

Authors

Elisa Erjavec¹, Clémentine Angée¹, Djihad Hadjadj², Bruno Passet³, Pierre David⁴, Corinne Kostic⁵, Emmanuel Dodé⁶, Xavier Zanlonghi⁶, Nicolas Cagnard⁷, Brigitte Nedelec¹, Sylvain V Crippa⁵, Christine Bole-Feysot⁸, Mohammed Zarhrate⁸, Sophie Creuzet⁹, Johan Castille³, Jean-Luc Vilotte³, Patrick Calvas¹⁰, Julie Plaisancié¹⁰, Nicolas Chassaing¹⁰, Josseline Kaplan¹, Jean-Michel Rozet¹¹, Lucas Fares Taie¹²

Affiliations

¹ Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Université Paris Cité, Paris, France.
² Institut Cochin, Inserm U1016, CNRS UMR8104, UFR de Pharmacie de Paris, Université Paris Cité, CARPEM, Paris, France.
³ University of Paris-Saclay, INRAE, AgroParisTech, UMR1313 GABI, Jouy-en-Josas, France.
⁴ Transgenesis Platform, Laboratoire d'Expérimentation Animale et Transgenèse (LEAT), Imagine Institute, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, Paris, France.
⁵ Group for Retinal Disorder Research, Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland.
⁶ Institut Ophtalmologique de L'Ouest-Clinique Jules VERNE, Nantes, France.
⁷ Université Paris Cité, Bioinformatics Core Facility, Imagine Institute, INSERM UMR 1163, Paris, France.
⁸ Université Paris Cité, Genomics Platform, Imagine Institute, INSERM UMR 1163, INSERM US24/CNRS UAR3633, Paris, France.
⁹ Paris-Saclay Institute of Neuroscience, NeuroPSI, CNRS, Paris-Saclay University, Campus CEA Saclay, Bât 151, 151 Route de la Rotonde, 91400 Saclay, France.
¹⁰ Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU Toulouse, Toulouse, France.
¹¹ Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Université Paris Cité, Paris, France. Electronic address: jean-michel.rozet@inserm.fr.
¹² Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Université Paris Cité, Paris, France. Electronic address: lucas.fares-taie@inserm.fr.

PMID: 39293448
DOI: 10.1016/j.ajhg.2024.08.019

Abstract

Congenital microcoria (MCOR) is a rare hereditary developmental defect of the iris dilator muscle frequently associated with high axial myopia and high intraocular pressure (IOP) glaucoma. The condition is caused by submicroscopic rearrangements of chromosome 13q32.1. However, the mechanisms underlying the failure of iris development and the origin of associated features remain elusive. Here, we present a 3D architecture model of the 13q32.1 region, demonstrating that MCOR-related deletions consistently disrupt the boundary between two topologically associating domains (TADs). Deleting the critical MCOR-causing region in mice reveals ectopic Sox21 expression precisely aligning with Dct, each located in one of the two neighbor TADs. This observation is consistent with the TADs' boundary alteration and adoption of Dct regulatory elements by the Sox21 promoter. Additionally, we identify Tgfb2 as a target gene of SOX21 and show TGFΒ2 accumulation in the aqueous humor of an MCOR-affected subject. Accumulation of TGFB2 is recognized for its role in glaucoma and potential impact on axial myopia. Our results highlight the importance of SOX21-TGFB2 signaling in iris development and control of eye growth and IOP. Insights from MCOR studies may provide therapeutic avenues for this condition but also for glaucoma and high myopia conditions, affecting millions of people.

Keywords: DCT enhancer adoption; SOX21-TGFB2 signalling glaucoma and myopia; Sox21 ectopic expression; congenital microcoria; developmental genetics; genetic eye disorders; genome architecture; mouse model; topologically-associated domain; translational medicine.