The eye primordium arises as a lateral outgrowth of the forebrain, with a transient fissure on the inferior side of the optic cup providing an entry point for developing blood vessels. Incomplete closure of the inferior ocular fissure results in coloboma, a disease characterized by gaps in the inferior eye and recognized as a significant cause of pediatric blindness. Here, we identify eight patients with defects in tissues of the superior eye, a congenital disorder that we term superior coloboma. The embryonic origin of superior coloboma could not be explained by conventional models of eye development, leading us to reanalyze morphogenesis of the dorsal eye. Our studies revealed the presence of the superior ocular sulcus (SOS), a transient division of the dorsal eye conserved across fish, chick, and mouse. Exome sequencing of superior coloboma patients identified rare variants in a Bone Morphogenetic Protein (Bmp) receptor (BMPR1A) and T-box transcription factor (TBX2). Consistent with this, we find sulcus closure defects in zebrafish lacking Bmp signaling or Tbx2b. In addition, loss of dorsal ocular Bmp is rescued by concomitant suppression of the ventral-specific Hedgehog pathway, arguing that sulcus closure is dependent on dorsal-ventral eye patterning cues. The superior ocular sulcus acts as a conduit for blood vessels, with altered sulcus closure resulting in inappropriate connections between the hyaloid and superficial vascular systems. Together, our findings explain the existence of superior coloboma, a congenital ocular anomaly resulting from aberrant morphogenesis of a developmental structure.

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Notes/Citation Information

Published in PLOS Genetics, v. 14, no. 3, e1007246, p. 1-28.

© 2018 Hocking et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Funding Information

This research was supported by operating grants from the Canadian Institutes of Health Research (CIHR, MOP #126191) and the Women and Children's Health Research Institute (WCHRI, #1706) to AJW and a University of Texas Systems Neuroscience Award (#365133) and a March of Dimes grant (FY16-169) to SA. JCH and JKF were supported by Alberta Innovates - Health Solutions (AIHS) fellowships, SAW and KHY by Natural Sciences and Engineering Research Council of Canada (NSERC) and Alberta Innovates - Technology Futures (AITF) scholarships, and SAW and by a WCHRI scholarship. FORGE sequencing was funded by Genome Canada, CIHR, the Ontario Genomic Institute (OGI-049), Genome Quebec, Genome BC and the McLaughlin Centre.

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All relevant data are within the paper and its Supporting Information files.

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S2 Table. Genetic variants in superior coloboma patients.

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S1 Fig. Genetic variants identified in bilateral superior coloboma patient.

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S2 Fig. Superior ocular sulcus in chick.

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S3 Fig. Superior ocular sulcus in newt.

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S4 Fig. Dynamics of the zebrafish superior ocular sulcus.

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S6 Fig. Human variant in BMPR1A reduces protein function.

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S1 Video. Superior ocular sulcus appears after optic cup and lens formation.

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S2 Video. Formation of the optic cup.

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S3 Video. Superior ocular sulcus transitions from narrow to wide.

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