loading page

Analysis of BMP3 variants in the causality of ocular coloboma
  • +7
  • Sabrina Fox,
  • Sonya Widen,
  • Mika Asai-Coakwell,
  • Serhiy Havrylov,
  • Matthew Benson,
  • Lisa Prichard,
  • Pranidhi Baddam,
  • Daniel Graf,
  • Ordan Lehmann,
  • Andrew J. Waskiewicz
Sabrina Fox
University of Alberta
Author Profile
Sonya Widen
University of Alberta
Author Profile
Mika Asai-Coakwell
University of Saskatchewan
Author Profile
Serhiy Havrylov
University of Alberta
Author Profile
Matthew Benson
University of Alberta
Author Profile
Lisa Prichard
MacEwan University
Author Profile
Pranidhi Baddam
University of Alberta
Author Profile
Daniel Graf
University of Alberta
Author Profile
Ordan Lehmann
University of Alberta
Author Profile
Andrew J. Waskiewicz
University of Alberta
Author Profile

Abstract

Coloboma, a congenital disorder characterized by gaps in ocular tissues, is caused when the choroid fissure fails to close during embryonic development. Several loci have been associated with coloboma, but these represent less than 40% of those that are involved with this disease. Here, we describe a novel coloboma-causing locus, BMP3. Whole exome sequencing and Sanger sequencing of patients with coloboma identified three variants in BMP3, two of which are predicted to be disease causing. Consistent with this, bmp3 mutant zebrafish have aberrant fissure closure. bmp3 is expressed in the ventral head mesenchyme and regulates phosphorylated Smad3 in a population of cells adjacent to the choroid fissure. Furthermore, mutations in bmp3 sensitize embryos to Smad3 inhibitor treatment resulting in open choroid fissures. Micro CT scans and Alcian blue staining of zebrafish demonstrate that mutations in bmp3 cause midface hypoplasia, suggesting that bmp3 regulates cranial neural crest cells. Consistent with this, we see active Smad3 in a population of periocular neural crest cells, and bmp3 mutant zebrafish have reduced neural crest cells in the choroid fissure. Taken together, this data suggests that Bmp3 controls Smad3 phosphorylation in neural crest cells to regulate early craniofacial and ocular development.