Donders Institute for Brain, Cognition and Behaviour
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Thesis series Dyah Karjosukarso (Donders series 383)

4 July 2019

Promotor: prof. dr. F. Cremers, dr. R. Collin
Co-promotor: dr. H. Zhou

Towards deeper molecular insight into familial exudative vitreoretinopathy: Zinc-ing deep into the vessel

Vision plays a crucial role in one’s life. The human eye consists of numerous delicate parts which have different functions. The retina is the part of the eye that is responsible to catch the light signal from the environment and convert it into neural impulses for the brain to perceive. The retina has a high metabolic activity, which is supported by nutrients supplied through blood vessels. This thesis focuses on a subtype of visual impairment termed familial exudative vitreoretinopathy (FEVR). It is an inherited retinal disorder hallmarked by abnormal or absence of vasculature in the peripheral retina.

A few years ago, a mutation in ZNF408(c.1363C>T, p.His455Tyr) was identified in an autosomal dominant FEVR family. Nevertheless, little is known about its molecular function.Transcriptome profiling showed that ZNF408 regulates the expression of genes relevant to the development of vasculature, which is altered by the p.His455Tyr mutation. To further study the function of znf408in vivo, znf408zebrafish models were generated.Characterization of the mutant models showed delayed retinal vasculature development at larval stage, abnormal sprouting in young adults, and vascular leakage in adults. These indicate the suitability of these models as animal model of FEVR and also to further study znf408in retinal vasculature development in vivo.

FEVR is a clinically and genetically heterogeneous disease. Furthermore, reduced penetrance has been observed in approximately 25% of mutation carriers in FEVR. It is still unclear what the underlying cause of the observed reduced penetrance is. A pilot study showed how patient-specific endothelial cells can be generated from induced pluripotent stem cells and that the obtained endothelial cells can be employed in studying reduced penetrance in FEVR. Additionally, a mutation in KIF11in a patient presenting FEVR and microcephaly was identified. Further genetic study revealed that the mutation was inherited from the unaffected mother who is mosaic for the mutation. This study showed the importance of thorough genetic assessment of unaffected parents, particularly in an isolated cases, to enable more reliable recurrence risk assessment and hence, better genetic counseling. Finally, the impact of the studies presented in this thesis to diagnostics, disease management, and potential therapeutics for FEVR are discussed.