University of Cambridge
Genetic, Cellular and Ultrastructural Mechanisms in Retinal Detachment
Abstract
dc:description.abstractRhegmatogenous retinal detachment (RRD) is a blinding eye condition, usually requiring emergency surgical repair. The proximate cause is a retinal tear caused by posterior vitreous detachment (PVD), but most people with PVD do not develop RRD. Understanding the underlying processes may help to prevent the need for emergency surgery and prevent vision loss. The work in this thesis uses three approaches to investigate the causes of RRD – genetic, ultrastructural and transcriptomic. Stickler syndrome is the most common form of hereditary RRD, usually from dominant variants in genes for type II and XI collagen. Here, two pedigrees with atypical mutation patterns are investigated. One family had a heterozygous *BMP4* variant identified, the first dominant non-collagen gene associated with Stickler syndrome. This suggests an underlying mechanism of RRD due to dysregulation of the TGFβ signalling pathway, as several other genes causing syndromic hereditary RRD link to this pathway. Another family had biallelic *COL11A1* variants identified, highlighting that variants affecting exon 9 will have a dominantly ocular effect, compensating for an otherwise lethal homozygous *COL11A1* null variant. The posterior hyaloid membrane (PHM) was extracted from cadaveric eyes with PVD and examined with scanning and transmission electron microscopy and compared to eyes with no PVD. The PHM was identified as a smooth, lacy structure with an integral population of laminocytes, similar in appearance to the ILM, consistent with its hypothesised origin as an anterior leaf of the ILM prior to separation. The findings also reinforce the importance of identification of PVD status for interpretation of post-mortem vitreous pathology, as in eyes without PVD the ILM can artefactually separate from the retina and encase the vitreous, potentially contaminating research assuming the presence of only vitreous gel. The integration of laminocytes within the PHM suggests they may be producing collagen as part of the membrane, or may play a role in the contraction and separation of PHM from retina in PVD. Cell populations associated with the PHM may play an active role in PVD and contribute to whether it is uncomplicated or associated with retinal detachment or vitreomaculopathies, including epiretinal membrane and macular hole. Using RNA-Seq, the transcriptome was analysed in surgical samples from patients having 1) vitrectomy for uncomplicated PVD, 2)_RRD, 3) epiretinal membrane, 4) macular hole and 5) vitreomacular traction. Limited conclusions could be drawn for uncomplicated PVD and RRD, but a novel finding of overexpression of integrins was identified in the epiretinal membrane samples. This is a potential treatment target to prevent progression of epiretinal membrane with associated distortion and blur and need for surgery.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Medicine (MD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2024
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Nixon, Thomas
- Advisor dc:contributor.advisor
-
- Snead, Martin
Subjects
dc:subject × 6Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.112393
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/374275