Underlying genetic mechanisms of hereditary dystrophies in retina and cornea
Inherited retinal and corneal dystrophies represent a group of disorders with great genetic heterogeneity. Over 250 genes are associated with retinal diseases and 16 genes are causative of corneal dystrophies. This thesis is focused on finding the genetic causes of corneal dystrophy, Leber congenita...
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Umeå universitet, Institutionen för medicinsk biovetenskap
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ftumeauniv:oai:DiVA.org:umu-130538 2023-10-09T21:54:31+02:00 Underlying genetic mechanisms of hereditary dystrophies in retina and cornea Frida, Jonsson 2017 application/pdf http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-130538 eng eng Umeå universitet, Institutionen för medicinsk biovetenskap Umeå : Umeå Universitet Umeå University medical dissertations, 0346-6612 1872 orcid:0000-0002-8899-2520 http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-130538 urn:isbn:978-91-7601-626-8 info:eu-repo/semantics/openAccess Cornea retina gene mutation detection inherited diseases Genetics Genetik Doctoral thesis, comprehensive summary info:eu-repo/semantics/doctoralThesis text 2017 ftumeauniv 2023-09-22T13:50:03Z Inherited retinal and corneal dystrophies represent a group of disorders with great genetic heterogeneity. Over 250 genes are associated with retinal diseases and 16 genes are causative of corneal dystrophies. This thesis is focused on finding the genetic causes of corneal dystrophy, Leber congenital amaurosis (LCA), Stargardt disease and retinitis pigmentosa in families from northern Sweden. By whole exome sequencing a novel mutation, c.2816C>T, p.Thr939Ile, in Collagen Type XVII, Alpha 1 chain, COL17A1, gene was identified in several families with epithelial recurrent erosion dystrophy (ERED). We showed that the COL17A1 protein is expressed in the basement membrane of the cornea, explaining the mutation involvement in the corneal symptoms. We could link all the families in this study to a couple born in the late 1700s confirming a founder mutation in northern Sweden. Our finding highlights role of COL17A1 in ERED and suggests screening of this gene in patients with similar phenotype worldwide. Furthermore the genetic causes in several retinal degenerations were identified. In one family with two recessive disorders, LCA and Stargardt disease, a novel stop mutation, c.2557C>T, p.Gln853Stop, was detected in all LCA patients. In the Stargardt patients two intronic variants, the novel c.4773+3A>G and c.5461-10T>C, were detected in the ABCA4 gene. One individual was homozygous for the known variant c.5461-10T>C and the other one was compound heterozygote with both variants present. Both variants, c.4773+3A>G and c.5461-10T>C caused exon skipping in HEK293T cells demonstrated by in vitro splice assay, proving their pathogenicity in Stargardt disease. Finally, in recessive retinitis pigmentosa, Bothnia Dystrophy (BD), we identified a second mutation in the RLBP1 gene, c.677T>A, p.Met226Lys. Thus, BD is caused not only by common c.700C>T variant but also by homozygosity of c.677T>A or compound heterozygosity. Notably, known variant, c.40C>T, p.R14W in the CAIV gene associated with a ... Doctoral or Postdoctoral Thesis Northern Sweden Umeå University: Publications (DiVA) |
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Umeå University: Publications (DiVA) |
op_collection_id |
ftumeauniv |
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Cornea retina gene mutation detection inherited diseases Genetics Genetik |
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Cornea retina gene mutation detection inherited diseases Genetics Genetik Frida, Jonsson Underlying genetic mechanisms of hereditary dystrophies in retina and cornea |
topic_facet |
Cornea retina gene mutation detection inherited diseases Genetics Genetik |
description |
Inherited retinal and corneal dystrophies represent a group of disorders with great genetic heterogeneity. Over 250 genes are associated with retinal diseases and 16 genes are causative of corneal dystrophies. This thesis is focused on finding the genetic causes of corneal dystrophy, Leber congenital amaurosis (LCA), Stargardt disease and retinitis pigmentosa in families from northern Sweden. By whole exome sequencing a novel mutation, c.2816C>T, p.Thr939Ile, in Collagen Type XVII, Alpha 1 chain, COL17A1, gene was identified in several families with epithelial recurrent erosion dystrophy (ERED). We showed that the COL17A1 protein is expressed in the basement membrane of the cornea, explaining the mutation involvement in the corneal symptoms. We could link all the families in this study to a couple born in the late 1700s confirming a founder mutation in northern Sweden. Our finding highlights role of COL17A1 in ERED and suggests screening of this gene in patients with similar phenotype worldwide. Furthermore the genetic causes in several retinal degenerations were identified. In one family with two recessive disorders, LCA and Stargardt disease, a novel stop mutation, c.2557C>T, p.Gln853Stop, was detected in all LCA patients. In the Stargardt patients two intronic variants, the novel c.4773+3A>G and c.5461-10T>C, were detected in the ABCA4 gene. One individual was homozygous for the known variant c.5461-10T>C and the other one was compound heterozygote with both variants present. Both variants, c.4773+3A>G and c.5461-10T>C caused exon skipping in HEK293T cells demonstrated by in vitro splice assay, proving their pathogenicity in Stargardt disease. Finally, in recessive retinitis pigmentosa, Bothnia Dystrophy (BD), we identified a second mutation in the RLBP1 gene, c.677T>A, p.Met226Lys. Thus, BD is caused not only by common c.700C>T variant but also by homozygosity of c.677T>A or compound heterozygosity. Notably, known variant, c.40C>T, p.R14W in the CAIV gene associated with a ... |
format |
Doctoral or Postdoctoral Thesis |
author |
Frida, Jonsson |
author_facet |
Frida, Jonsson |
author_sort |
Frida, Jonsson |
title |
Underlying genetic mechanisms of hereditary dystrophies in retina and cornea |
title_short |
Underlying genetic mechanisms of hereditary dystrophies in retina and cornea |
title_full |
Underlying genetic mechanisms of hereditary dystrophies in retina and cornea |
title_fullStr |
Underlying genetic mechanisms of hereditary dystrophies in retina and cornea |
title_full_unstemmed |
Underlying genetic mechanisms of hereditary dystrophies in retina and cornea |
title_sort |
underlying genetic mechanisms of hereditary dystrophies in retina and cornea |
publisher |
Umeå universitet, Institutionen för medicinsk biovetenskap |
publishDate |
2017 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-130538 |
genre |
Northern Sweden |
genre_facet |
Northern Sweden |
op_relation |
Umeå University medical dissertations, 0346-6612 1872 orcid:0000-0002-8899-2520 http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-130538 urn:isbn:978-91-7601-626-8 |
op_rights |
info:eu-repo/semantics/openAccess |
_version_ |
1779318115211935744 |