Abstract
Pterygium is a pathological condition of the ocular surface of the eye, characterized by a highly vascularized and fibrovascular tissue formation arising from the limbus and invading the central cornea. Despite the controversy about pterygium patho-mechanism, UV exposure represents the main trigger for this uncontrolled overgrowth, mainly due to the high incidence of the disease around the equatorial areas. However, in certain families a much higher susceptibility to developing pterygium has been observed, suggesting a genetic etiologic component.In this study, a Northern Irish family affected in three generations by pterygium and yet rarely exposed to direct UV light was identified. Whole Exome Sequencing and subsequent bioinformatic analysis, literature review and expression analysis prioritised a novel missense variant (p.H412P) in CRIM1 gene, encoding for a type I transmembrane protein, which co-segregates with the disease within the family. A higher CRIM1 expression was shown in pterygium tissues with respect to the conjunctival controls in the North European (low UV-exposure) population and another missense mutation in CRIM1, R745C, was identified in an individual pterygium patient from Bolivia.
In vitro functional analysis showed an antiproliferative and proapoptotic role for CRIM1 overexpression, which is able to modulate the extracellular signal–regulated kinases (ERK) phosphorylation induced by UV light. For the first time CRIM1 expression revealed an pivotal role in UV mediated intracellular ERK pathway and apoptosis; pathway which was already documented in pterygium and which resulted in an impaired function when introducing H412P mutation in CRIM1, reinforcing the significance of this mutation identified in the Northern Irish pterygium family.
| Date of Award | Jul 2016 |
|---|---|
| Original language | English |
| Supervisor | Sarah Atkinson (Supervisor), Tara Moore (Supervisor) & Andrew Nesbit (Supervisor) |