Deletion upstream of MAB21L2 highlights the importance of evolutionarily conserved non-coding sequences for eye development

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 Baere, Patrick Calvas, Kris Vleminckx (), Elena V. Semina () and Nicola K. Ragge ()
Additional contact information
Fabiola Ceroni: Oxford Brookes University
Munevver B. Cicekdal: Ghent University
Richard Holt: Oxford Brookes University
Elena Sorokina: Medical College of Wisconsin
Nicolas Chassaing: CHU Toulouse
Samuel Clokie: Oxford Brookes University
Thomas Naert: Ghent University
Lidiya V. Talbot: Oxford Brookes University
Sanaa Muheisen: Medical College of Wisconsin
Dorine A. Bax: Oxford Brookes University
Yesim Kesim: Oxford Brookes University
Emma C. Kivuva: Royal Devon University Healthcare NHS Foundation Trust
Catherine Vincent-Delorme: Hôpital Jeanne de Flandre
Soeren S. Lienkamp: University of Zurich
Julie Plaisancié: CHU Toulouse
Elfride Baere: Ghent University Hospital
Patrick Calvas: CHU Toulouse
Kris Vleminckx: Ghent University
Elena V. Semina: Medical College of Wisconsin
Nicola K. Ragge: Oxford Brookes University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53553-2

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