Deletion upstream of MAB21L2 highlights the importance of evolutionarily conserved non-coding sequences for eye development
Résumé
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.
Anophthalmia (absent eye), microphthalmia (small eye) and coloboma (disruption of optic fissure closure) (AMC) form a phenotypic spectrum of developmental disorders affecting ~6-30 per 100,000 live births 1,2 , and account for up to 20% of childhood visual impairment 2 . While genetic variants affecting the transcription factors SOX2 and OTX2 represent the most common causes of AMC, explaining 10-15% and 2-5% of cases, respectively 2 , these conditions are genetically highly heterogeneous, with at least 130 genes currently included in standard structural eye disorders diagnostic panels (for example, https://panelapp.genomicsengland.co.uk/panels/509/). Despite
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Sciences du Vivant [q-bio]| Origine | Fichiers produits par l'(les) auteur(s) |
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