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

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.

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Nature Communications
Published
2024-10-26
DOI
https://doi.org/10.1038/s41467-024-53553-2
Citations
6
Primary Topic
Genomic variations and chromosomal abnormalities
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article
Field-Weighted Citation Impact
3.30

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article

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

Yeşim Kesim, Emma Kivuva, Elena V. Semina, Samuel Clokie et al.
6 citations
Nature Communications
Genomic variations and chromosomal abnormalities
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article

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

Yeşim Kesim, Emma Kivuva, Elena V. Semina, Samuel Clokie, Julie Plaisancié, Patrick Calvas, Dorine A. Bax, Lidiya V. Talbot, Елена А. Сорокина, Richard Holt, Munevver Burcu Cicekdal, Soeren S. Lienkamp, Sanaa Muheisen, Nicolas Chassaing, Kris Vleminckx, Thomas Naert, Elfride De Baere, Catherine Vincent-Delorme, Nicola Ragge, Fabiola Ceroni
article en
6 citations

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.

Nature CommunicationsVol. 15(1)
Oxford Brookes University (GB), Centre National de la Recherche Scientifique (FR), Centre for Human Genetics (GB), Université Toulouse III - Paul Sabatier (FR), University of Zurich (CH), Medical College of Wisconsin (US), Royal Devon & Exeter NHS Foundation Trust (GB), Ghent University Hospital (BE), John Radcliffe Hospital (GB), Centre Hospitalier Universitaire de Toulouse (FR), Ghent University (BE), University of Oxford (GB), Centre de Biologie du Développement (FR), Hôpital Jeanne de Flandre (FR), Hôpital Purpan (FR), Oxford BioMedica (United Kingdom) (GB), Birmingham Women’s and Children’s NHS Foundation Trust (GB), University of Bologna (IT)
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
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Genomic variations and chromosomal abnormalities
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