July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Mutation of Bmp3 represents a novel cause of ocular coloboma
Author Affiliations & Notes
  • Lisa Prichard
    Department of Biological Sciences, MacEwan University, Edmonton, Alberta, Canada
  • Sonya Widen
    Department of Biological Sciences, University of Alberta, Alberta, Canada
  • Ordan J Lehmann
    Department of Medical Genetics, University of Alberta, Alberta, Canada
  • Andrew Waskiewicz
    Department of Biological Sciences, University of Alberta, Alberta, Canada
  • Footnotes
    Commercial Relationships   Lisa Prichard, None; Sonya Widen, None; Ordan Lehmann, None; Andrew Waskiewicz, None
  • Footnotes
    Support  NSERC
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 6028. doi:
  • Views
  • Share
  • Tools
    • Alerts
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Lisa Prichard, Sonya Widen, Ordan J Lehmann, Andrew Waskiewicz; Mutation of Bmp3 represents a novel cause of ocular coloboma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6028.

      Download citation file:

      © ARVO (1962-2015); The Authors (2016-present)

  • Supplements

Purpose : Ocular coloboma results from the incomplete fusion of the optic fissure and is a major cause of pediatric vision loss. We investigated a microphthalmia, anophthalmia and coloboma (MAC) cohort to advance understanding of these disorders’ genetic etiology.

Methods : Exomic next generation sequencing (NGS) was performed in a large coloboma pedigree and the mutated gene was subsequently screened in 150 MAC DNA samples. Luciferase reporter assays, western blots and in silico ANOLEA modeling were used to investigate the pathogenicity of the identified mutations. Zebrafish morpholino (MO) inhibition was used to investigate gene function together with in situ hybridization (ISH), and analysis of transgenic GFP reporter lines.

Results : NGS identified a BMP3 mutation in all affected individuals, which alters a residue invariant in all vertebrates (A470P). Two additional variants were identified in the larger cohort (S393F, F450Y), all of which were absent from controls. Consistent with these variants being disease causing, western immunoblots demonstrate significant alterations in activity relative to wildtype BMP3. We show that bmp3 is expressed in a periocular population of cells ventral and nasal to the developing eye. Supporting bmp3’s role in ocular development, coloboma is present in both Bmp3 morpholino knockdown and CRISPR knockout bmp3-/- embryos. We posit that the function of Bmp3 is to regulate Smad3 phosphorylation in ventronasal migratory periocular cells. Consistent with this, we also observe coloboma in embryos treated with SIS3, an inhibitor of Smad3.

Conclusions : We have identified a novel gene involved in MAC disorders, BMP3. While the precise regulation of ocular BMPs is required for optic fissure closure, BMP3’s role in eye development and disease was previously unstudied. Our research extends the role of BMPs in eye development and implicates BMP signaling in periocular cells.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.