ZFIN ID: ZDB-PUB-200226-11
Modeling ZNF408-Associated FEVR in Zebrafish Results in Abnormal Retinal Vasculature
Karjosukarso, D.W., Ali, Z., Peters, T.A., Zhang, J.Q.C., Hoogendoorn, A.D.M., Garanto, A., van Wijk, E., Jensen, L.D., Collin, R.W.J.
Date: 2020
Source: Investigative ophthalmology & visual science   61: 39 (Journal)
Registered Authors: Collin, Rob, Hoogendoorn, Anita, Karjosukarso, Dyah, van Wijk, Erwin
Keywords: none
MeSH Terms:
  • Animals
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/physiology*
  • Familial Exudative Vitreoretinopathies*/genetics
  • Familial Exudative Vitreoretinopathies*/physiopathology
  • Mutation, Missense
  • Retinal Vessels/pathology*
  • Zebrafish
PubMed: 32097476 Full text @ Invest. Ophthalmol. Vis. Sci.
Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disease in which the retinal vasculature is affected. Patients with FEVR typically lack or have abnormal vasculature in the peripheral retina, the outcome of which can range from mild visual impairment to complete blindness. A missense mutation (p.His455Tyr) in ZNF408 was identified in an autosomal dominant FEVR family. Little, however, is known about the molecular role of ZNF408 and how its defect leads to the clinical features of FEVR.
Using CRISPR/Cas9 technology, two homozygous mutant zebrafish models with truncated znf408 were generated, as well as one heterozygous and one homozygous missense znf408 model in which the human p.His455Tyr mutation is mimicked.
Intriguingly, all three znf408-mutant zebrafish strains demonstrated progressive retinal vascular pathology, initially characterized by a deficient hyaloid vessel development at 5 days postfertilization (dpf) leading to vascular insufficiency in the retina. The generation of stable mutant lines allowed long-term follow up studies, which showed ectopic retinal vascular hyper-sprouting at 90 dpf and extensive vascular leakage at 180 dpf.
Together, our data demonstrate an important role for znf408 in the development and maintenance of the vascular system within the retina.