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

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

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Division of Anatomy, Department of Surgery, University of Alberta, Edmonton, Canada.
Women & Children's Health Research Institute, University of Alberta, Edmonton, Canada.
Department of Biological Sciences, University of Alberta, Edmonton, Canada.
Department of Medical Genetics, University of Alberta, Edmonton, Canada.
Department of Biology, University of Kentucky, Lexington, Unites States of America.
Department of Molecular Biosciences, University of Texas at Austin,Unites States of America.
Department of Medical Neurobiology, Institute for Medical Research-Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, Unites States of America.
Institute for Neuroscience, University of Texas at Austin, Austin, Unites States of America.
Department of Ophthalmology, University of Alberta, Edmonton, Canada.
Neuroscience and Mental Health Research Institute, University of Alberta, Edmonton, Canada.


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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