Morphogenetic defects underlie Superior Coloboma, a newly identified closure disorder of the dorsal eye

PLoS Genet. 2018 Mar 9;14(3):e1007246. doi: 10.1371/journal.pgen.1007246. eCollection 2018 Mar.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Adult
  • Animals
  • Animals, Genetically Modified
  • Bone Morphogenetic Protein Receptors, Type I / genetics*
  • Bone Morphogenetic Protein Receptors, Type I / metabolism
  • Chick Embryo
  • Coloboma / embryology*
  • Coloboma / genetics*
  • Cytochrome P-450 CYP1B1 / genetics*
  • Embryo, Nonmammalian
  • Eye / embryology*
  • Growth Differentiation Factor 6 / genetics
  • Growth Differentiation Factor 6 / metabolism
  • Humans
  • Infant
  • Mice
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism


  • Growth Differentiation Factor 6
  • T-Box Domain Protein 2
  • T-Box Domain Proteins
  • Zebrafish Proteins
  • gdf6a protein, zebrafish
  • tbx2a protein, zebrafish
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1B1
  • BMPR1A protein, human
  • Bone Morphogenetic Protein Receptors, Type I

Grant support

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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.