MAC

Ocular coloboma (OC) is a failure of complete optic fissure closure during embryonic development and presents as a tissue defect along the proximal distal axis of the ventral eye. It is classed as part of the clinical spectrum of structural eye malformations with microphthalmia and anophthalmia, collectively abbreviated to MAC. Despite deliberate attempts to identify causative variants in MAC, many patients remain without a genetic diagnosis. To reveal potential candidate genes, we utilised transcriptomes experimentally generated from embryonic eye tissues derived from human, mouse, zebrafish, and chicken at stages coincident with optic fissure closure

Investigation of the molecular pathology of oculogenesis regulator, PAX6, through patient-derived hiPSC optic vesicles with (i) haploinsufficiency-related aniridia and (ii) missense-associated microphthalmia. Transcriptomic analysis reveals variant-specific disruption to SOX2-mediated Notch-signalling perturbing proliferation and differentiation, uncovering a mechanism for PAX6-associated microphthalmia.

Ocular coloboma arises from genetic or environmental perturbations which inhibit optic fissure fusion in early eye development. Despite high genetic heterogeneity, 70-85% of patients remain molecularly undiagnosed. We report BMPR1B as a novel causative gene using cross-species comparative meta-analysis.

Eye morphogenesis is tightly regulated by a highly conserved genetic network that when disrupted, can result in severe ocular malformation on a spectrum known as microphthalmia, anophthalmia and coloboma (MAC). Using RNA-seq, we detected upregulation of pro-apoptotic genes in microphthalmia optic vesicles. Dysregulation of Notch signalling modulated through an ASCL1 negative feedback loop between the DLL ligand and HES effector families was also common between microphthalmia samples. This resulted in differential expression of Notch target genes such as MITF and HDAC1. Additionally, the increased production of extracellular matrix (ECM) components such as collagen and laminin, resulting in ECM abnormalities, was detected in microphthalmia optic vesicles.