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Underlying genetic mechanisms of hereditary dystrophies in retina and cornea / Frida Jonsson

Frida, Jonsson, 1979- (författare)
Umeå universitet. Institutionen för medicinsk biovetenskap (utgivare)
Umeå universitet. Institutionen för klinisk vetenskap (utgivare)
ISBN 978-91-7601-626-8
Umeå : Umeå Universitet, 2017
Engelska 57 s.
Serie: [Umeå University medical dissertations], 0346-6612 ; N.S., 1872
  • BokAvhandling(Diss. (sammanfattning) Umeå : Umeå universitet, 2017)
Sammanfattning Ämnesord
  • 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 dominant retinal dystrophy RP17 was detected in one of the compound BD heterozygote and his unaffected mother. This variant appears to be a benign variant in the population of northern Sweden. In conclusion, novel genetic causes of retinal dystrophies in northern Sweden were found demonstrating the heterogeneity and complexity of retinal diseases. Identification of the genetic defect in COL17A1 in the corneal dystrophy contributes to understanding ERED pathogenesis and encourages refinement of IC3D classification. Our results provide valuable information for future molecular testing and genetic counselling of the families. 


Carbonic anhydrase IV  -- genetics (MeSH)
Carrier proteins  -- genetics (MeSH)
Genes, recessive  (MeSH)
Heterozygote  (MeSH)
Mutation  -- genetics (MeSH)
Retinitis pigmentosa  -- genetics (MeSH)
ATP-binding cassette transporters  -- genetics (MeSH)
Eye proteins  -- genetics (MeSH)
Genetic predisposition to disease  (MeSH)
Leber congenital amaurosis  -- genetics (MeSH)
Macular degeneration  -- congenital (MeSH)
Membrane proteins  -- genetics (MeSH)
Nerve tissue proteins  -- genetics (MeSH)
Autoantigens  -- genetics (MeSH)
Corneal dystrophies, hereditary  -- diagnosis (MeSH)
Corneal dystrophies, hereditary  -- genetics (MeSH)
Epithelium, corneal  -- pathology (MeSH)
Genetic association studies  (MeSH)
Non-fibrillar collagens  -- genetics (MeSH)

Indexterm och SAB-rubrik

Mutation detection
Inherited diseases


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Frida, Jonsson, 1979 ...
Umeå universitet. In ...
Umeå universitet. In ...
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Carbonic anhydrase IV
Carbonic anhydrase I ...
och genetics
Carrier proteins
Carrier proteins
och genetics
Genes, recessive
och genetics
Retinitis pigmentosa
Retinitis pigmentosa
och genetics
visa fler...
ATP-binding cassette transporters
ATP-binding cassette ...
och genetics
Eye proteins
Eye proteins
och genetics
Genetic predispositi ...
Leber congenital amaurosis
Leber congenital ama ...
och genetics
Macular degeneration
Macular degeneration
och congenital
Membrane proteins
Membrane proteins
och genetics
Nerve tissue proteins
Nerve tissue protein ...
och genetics
och genetics
Corneal dystrophies, hereditary
Corneal dystrophies, ...
och diagnosis
Corneal dystrophies, hereditary
Corneal dystrophies, ...
och genetics
Epithelium, corneal
Epithelium, corneal
och pathology
Genetic association ...
Non-fibrillar collagens
Non-fibrillar collag ...
och genetics
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Underlying genetic m ...

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