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

• Published in: American journal of human genetics pp. S0002 - 9297(24)00305-7
• Main Authors: Erjavec, Elisa, Angée, Clémentine, Hadjadj, Djihad, Passet, Bruno, David, Pierre, Kostic, Corinne, Dodé, Emmanuel, Zanlonghi, Xavier, Cagnard, Nicolas, Nedelec, Brigitte, Crippa, Sylvain V, Bole-Feysot, Christine, Zarhrate, Mohammed, Creuzet, Sophie, Castille, Johan, Vilotte, Jean-Luc, Calvas, Patrick, Plaisancié, Julie, Chassaing, Nicolas, Kaplan, Josseline, Rozet, Jean-Michel, Taie, Lucas Fares
• Format: Journal Article
• Language: English
• Published: Elsevier (Cell Press) 13.09.2024
• Subjects: Life Sciences; Sox21 ectopic expression; genetic eye disorders; translational medicine; mouse model; topologically-associated domain; developmental genetics; congenital microcoria; DCT enhancer adoption; SOX21-TGFB2 signalling glaucoma and myopia; genome architecture
• ISSN: 1537-6605; 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2024.08.019

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.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.