Deletion upstream of MAB21L2 highlights the importance of evolutionarily conserved non-coding sequences for eye development
Year: 2024
Type: article
Abstract: Anophthalmia, microphthalmia and coloboma (AMC) comprise a spectrum of developmental eye disorders, accounting for approximately 20% of childhood visual impairment. While non-coding regulatory sequences are increasingly recognised as contributing to disease burden, characterising their impact on gene function and phenotype remains challenging. Furthermore, little is known of the nature and extent of their contribution to AMC phenotypes. We report two families with variants in or near MAB21L2, a gene where genetic variants are known to cause AMC in humans and animal models. The first proband, presenting with microphthalmia and coloboma, has a likely pathogenic missense variant (c.338 G > C; p.[Trp113Ser]), segregating within the family. The second individual, presenting with microphthalmia, carries an ~ 113.5 kb homozygous deletion 19.38 kb upstream of MAB21L2. Modelling of the deletion results in transient small lens and coloboma as well as midbrain anomalies in zebrafish, and microphthalmia and coloboma in Xenopus tropicalis. Using conservation analysis, we identify 15 non-coding conserved elements (CEs) within the deleted region, while ChIP-seq data from mouse embryonic stem cells demonstrates that two of these (CE13 and 14) bind Otx2, a protein with an established role in eye development. Targeted disruption of CE14 in Xenopus tropicalis recapitulates an ocular coloboma phenotype, supporting its role in eye development. Together, our data provides insights into regulatory mechanisms underlying eye development and highlights the importance of non-coding sequences as a source of genetic diagnoses in AMC.
Source: Nature Communications
Authors: Fabiola Ceroni, Munevver B. Cicekdal, Richard Holt, Elena Sorokina, Nicolas Chassaing, Samuel Clokie, Thomas Naert, Lidiya V. Talbot, Sanaa Muheisen, Dorine A. Bax, Yesim Kesim, Emma C. Kivuva, Catherine Vincent-Delorme, Soeren S. Lienkamp, Julie Plaisancié, Elfride De Baere, Patrick Calvas, Kris Vleminckx, Elena V. Semina, Nicola K. Ragge
Institutions: Oxford Brookes University, University of Bologna, Ghent University Hospital, Ghent University, Medical College of Wisconsin, Centre Hospitalier Universitaire de Toulouse, Hôpital Purpan, University of Zurich, Centre for Human Genetics, John Radcliffe Hospital, University of Oxford, NIHR Oxford Biomedical Research Centre, Royal Devon University Healthcare NHS Foundation Trust, Hôpital Jeanne de Flandre, Centre National de la Recherche Scientifique, Université Toulouse III - Paul Sabatier, Centre de Biologie du Développement, Université de Toulouse, Centre de Biologie Intégrative de Toulouse, Birmingham Women's Hospital, Birmingham Women’s and Children’s NHS Foundation Trust
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: National Science Foundation, Oxford Brookes University, National Institute for Health and Care Research, European Commission, Agence Nationale de la Recherche, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Fonds Wetenschappelijk Onderzoek, Universiteit Gent, Universität Zürich, Vlaamse regering, Moorfields Eye Hospital NHS Foundation Trust, National Institutes of Health, Horizon 2020 Framework Programme, Bijzonder Onderzoeksfonds UGent, National Eye Institute
Awards: G1237028612, Cohorte nationale maladies rares, G1476683338, CRISPR/Cas9 based kidney disease modeling to elucidate novel genetic drivers and therapeutic targets in X. tropicalis, G198528871, G434337789, G4937468798, G5437185851, G6514882, MAB21L Family in Human Ocular Disease and Development, G7240651115, G798720511, G8004201094, G8271392683, European Training Network to Diagnose, Understand and Treat Stargardt Disease, a Frequent Inherited Blinding Disorder, G8858395165, G8863713643, Conserved transcriptional networks of tubulogenesis – towards a mechanistic understanding of renal malformations., Molecular mechanisms of anterior segment disorders, G9000172282, Genomic duplications in anophthalmia, microphthalmia and coloboma
OpenAlex ID: W4403794159