Genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies
Inherited eye disorders (IED) are groups of genetically and clinically heterogenous conditions affecting different tissues in the eye. IED are most often progressive with reduced vision or legal blindness as outcome. This thesis is focused on investigating the underlying mechanisms in Fuchs’ endothe...
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Umeå universitet, Medicinsk och klinisk genetik
2022
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ftumeauniv:oai:DiVA.org:umu-200205 2023-10-09T21:54:32+02:00 Genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies Genetik, epigenetik och funktionella mekanismer i ärftliga corneala och retinala dystrofier Westin, Ida Maria 2022 application/pdf http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-200205 eng eng Umeå universitet, Medicinsk och klinisk genetik Umeå universitet, Oftalmiatrik Umeå University Umeå : Umeå University Umeå University medical dissertations, 0346-6612 2187 orcid:0000-0001-8454-802X http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-200205 urn:isbn:978-91-7855-810-0 urn:isbn:978-91-7855-811-7 info:eu-repo/semantics/openAccess Genetics Epigenetics Splicing Methylation Ophtalmology FECD Stargardt Retinitis pigmentosa ABCA4 EYS TCF4 F5 THBD Coagulation factor V Thrombomodulin Medical Genetics Medicinsk genetik Ophthalmology Oftalmologi Doctoral thesis, comprehensive summary info:eu-repo/semantics/doctoralThesis text 2022 ftumeauniv 2023-09-22T13:56:20Z Inherited eye disorders (IED) are groups of genetically and clinically heterogenous conditions affecting different tissues in the eye. IED are most often progressive with reduced vision or legal blindness as outcome. This thesis is focused on investigating the underlying mechanisms in Fuchs’ endothelial corneal dystrophy (FECD) and two retinal dystrophies, Stargardt disease (STGD1) and autosomal recessive Retinitis pigmentosa (arRP, RP25). In FECD, we studied the association between FECD and the (CTG)n repeat expansion at the CTG18.1 locus in the TCF4 gene, in patients from northern Sweden. By using STR-PCR and TP-PCR, we found that 90% of FECD patients carry an expanded CTG18.1 allele, establishing the highest prevalence among FECD patients world-wide. With droplet digital PCR, we showed that transcripts spanning over the CTG18.1 have lower fractions in human corneal endothelium (CE) compared to skin, brain, muscle, and white blood cells. With Illumina Methylation arrays (850K), we detected a decreased global methylation in the CE at advanced age, that could possibly contribute to the late onset of FECD. We also found distinct differences in methylation between FECD patients and controls, that led us to two coagulation factors, found to be over-expressed in the CE from FECD patients. For the two retinal dystrophies, STGD1 and RP25, we investigated the functional effect of four genetic variants residing adjacent to or in splice consensus sequence of the ABCA4 gene (STDG1) and the EYS gene (RP25). With an in vitro mini-gene splicing assay we showed that all four genetic variants caused exon skipping in Retinal Pigment Epithelial cell line (ARPE-19) and Human Embryonic kidney cell line (HEK293T). Our results functionally proved these variants to be pathogenic and causative of STGD1 and RP25. In RP25, we also investigated the prevalence of pathogenic EYS variants in a cohort of patients from northern Sweden. DNA from 81 patients with a clinical diagnosis of RP were interrogated with a "cascade-targeted mutation ... Doctoral or Postdoctoral Thesis Northern Sweden Umeå University: Publications (DiVA) Fuchs ENVELOPE(-68.666,-68.666,-67.233,-67.233) |
institution |
Open Polar |
collection |
Umeå University: Publications (DiVA) |
op_collection_id |
ftumeauniv |
language |
English |
topic |
Genetics Epigenetics Splicing Methylation Ophtalmology FECD Stargardt Retinitis pigmentosa ABCA4 EYS TCF4 F5 THBD Coagulation factor V Thrombomodulin Medical Genetics Medicinsk genetik Ophthalmology Oftalmologi |
spellingShingle |
Genetics Epigenetics Splicing Methylation Ophtalmology FECD Stargardt Retinitis pigmentosa ABCA4 EYS TCF4 F5 THBD Coagulation factor V Thrombomodulin Medical Genetics Medicinsk genetik Ophthalmology Oftalmologi Westin, Ida Maria Genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies |
topic_facet |
Genetics Epigenetics Splicing Methylation Ophtalmology FECD Stargardt Retinitis pigmentosa ABCA4 EYS TCF4 F5 THBD Coagulation factor V Thrombomodulin Medical Genetics Medicinsk genetik Ophthalmology Oftalmologi |
description |
Inherited eye disorders (IED) are groups of genetically and clinically heterogenous conditions affecting different tissues in the eye. IED are most often progressive with reduced vision or legal blindness as outcome. This thesis is focused on investigating the underlying mechanisms in Fuchs’ endothelial corneal dystrophy (FECD) and two retinal dystrophies, Stargardt disease (STGD1) and autosomal recessive Retinitis pigmentosa (arRP, RP25). In FECD, we studied the association between FECD and the (CTG)n repeat expansion at the CTG18.1 locus in the TCF4 gene, in patients from northern Sweden. By using STR-PCR and TP-PCR, we found that 90% of FECD patients carry an expanded CTG18.1 allele, establishing the highest prevalence among FECD patients world-wide. With droplet digital PCR, we showed that transcripts spanning over the CTG18.1 have lower fractions in human corneal endothelium (CE) compared to skin, brain, muscle, and white blood cells. With Illumina Methylation arrays (850K), we detected a decreased global methylation in the CE at advanced age, that could possibly contribute to the late onset of FECD. We also found distinct differences in methylation between FECD patients and controls, that led us to two coagulation factors, found to be over-expressed in the CE from FECD patients. For the two retinal dystrophies, STGD1 and RP25, we investigated the functional effect of four genetic variants residing adjacent to or in splice consensus sequence of the ABCA4 gene (STDG1) and the EYS gene (RP25). With an in vitro mini-gene splicing assay we showed that all four genetic variants caused exon skipping in Retinal Pigment Epithelial cell line (ARPE-19) and Human Embryonic kidney cell line (HEK293T). Our results functionally proved these variants to be pathogenic and causative of STGD1 and RP25. In RP25, we also investigated the prevalence of pathogenic EYS variants in a cohort of patients from northern Sweden. DNA from 81 patients with a clinical diagnosis of RP were interrogated with a "cascade-targeted mutation ... |
format |
Doctoral or Postdoctoral Thesis |
author |
Westin, Ida Maria |
author_facet |
Westin, Ida Maria |
author_sort |
Westin, Ida Maria |
title |
Genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies |
title_short |
Genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies |
title_full |
Genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies |
title_fullStr |
Genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies |
title_full_unstemmed |
Genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies |
title_sort |
genetics, epigenetics and functional mechanisms in inherited corneal and retinal dystrophies |
publisher |
Umeå universitet, Medicinsk och klinisk genetik |
publishDate |
2022 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-200205 |
long_lat |
ENVELOPE(-68.666,-68.666,-67.233,-67.233) |
geographic |
Fuchs |
geographic_facet |
Fuchs |
genre |
Northern Sweden |
genre_facet |
Northern Sweden |
op_relation |
Umeå University medical dissertations, 0346-6612 2187 orcid:0000-0001-8454-802X http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-200205 urn:isbn:978-91-7855-810-0 urn:isbn:978-91-7855-811-7 |
op_rights |
info:eu-repo/semantics/openAccess |
_version_ |
1779318124647022592 |