The genes and molecules behind ‘keyhole’ eye development

Research details

  • Type of funding: Early Career Investigator Award
  • Grant Holder: Dr Joe Rainger
  • Institute: University of Edinburgh
  • Region: Scotland
  • Start date: October 2015
  • End Date: September 2018
  • Priority: Causes
  • Eye Category: Childhood-onset


People with the most common form of ocular coloboma have a gap at the base of the eye that means the iris is shaped like a keyhole instead of being round. The gap happens if the eye hasn’t fully closed during development in the womb. It may also extend further into the eye, including the retina (the light-sensitive layer) and the optic nerve (the specialised cable that passes visual signals from eye to brain), in which case it severely affects vision.

Ocular coloboma is the most common eye condition affecting European children and accounts for up to 10% of blindness. But we don’t yet know much about the genetic causes. So in this study the researcher is looking at the genes and molecules involved when the eye closes normally, try to find out what can go wrong and whether it can be fixed.

Results from the project should give us a much clearer idea of what’s needed for the eye to close correctly. It should also make it possible to relate people’s genetic data to the signs and symptoms they have. People with ocular coloboma may be able to have an accurate genetic diagnosis, and there may also be new potential targets for treatment.

  • Scientific summary

    Elucidating the genetic and molecular causes of human ocular coloboma

    Ocular coloboma is the most common major eye malformation and arises due to failure of embryonic optic fissure closure (OFC) in the developing eye, yet the majority of cases remain genetically undiagnosed. To alleviate this, major sequencing strategies are currently being applied to identify causative mutations in coloboma patients, however these will be restricted in their interpretation without improved knowledge of the critical processes required for OFC and robust data to illustrate their pathogenicity.

    This fellowship aims to develop a framework of the molecular and physical mechanisms of fissure closure from which human genetic data can be interpreted. As an exemplar, changes identified in actin-pathway genes are being assessed to determine how the mutations affect their normal function, and what their requirement is in the developing eye. Dr Rainger intendes to perform high-resolution characterisation of gene expression for known coloboma genes in the developing eye, and apply transcriptome-wide analysis to microdissected regions of the fissure margin to identify novel genes and genetic pathways that control optic fissure.

    This will augment disease-gene identification and provide valuable information to support subsequent hypothesis-driven research. The last objective is to replicate and microscopically visualise OFC in real-time using chick-eye explant culture, and to apply this to model human coloboma aetiology through genetic and chemical manipulations informed by the previous work, with the longer-term application of exploring mechanisms of phenotype reversal and prevention. This work will strongly support coloboma gene identification, and significantly enhance our basic understanding of OFC, broader eye development, and ocular diseases.