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Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
UCL Institute of Ophthalmology, London, UK.
Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.ORCID-id: 0000-0002-6091-3982
Visa övriga samt affilieringar
2015 (Engelska)Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 4, s. 463-473Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2015. Vol. 36, nr 4, s. 463-473
Nyckelord [en]
COL17A1, BP180, cornea dystrophy, ERED, ddPCR
Nationell ämneskategori
Medicinsk biovetenskap
Identifikatorer
URN: urn:nbn:se:umu:diva-103155DOI: 10.1002/humu.22764ISI: 000352304200011PubMedID: 25676728Scopus ID: 2-s2.0-84925859470OAI: oai:DiVA.org:umu-103155DiVA, id: diva2:815161
Anmärkning

Contract grant sponsors: Umeå University and Västerbotten County Council, Research and Development Foundation sponsored by Västerbotten County Council, Cronqvists Stiftelse (administered by The Swedish Society of Medicine); Ögonfonden, Stiftelsen KMA; the National Swedish Research Council (521-2013-2612); National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology; Moorfields Special Trustees; Moorfields Eye Charity; the Lanvern foundation.

Tillgänglig från: 2015-05-29 Skapad: 2015-05-18 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Ingår i avhandling
1. Underlying genetic mechanisms of hereditary dystrophies in retina and cornea
Öppna denna publikation i ny flik eller fönster >>Underlying genetic mechanisms of hereditary dystrophies in retina and cornea
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet, 2017. s. 57
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1872
Nyckelord
Cornea, retina, gene, mutation detection, inherited diseases
Nationell ämneskategori
Genetik
Forskningsämne
genetik
Identifikatorer
urn:nbn:se:umu:diva-130538 (URN)978-91-7601-626-8 (ISBN)
Disputation
2017-02-17, Major Groove, Målpunkt J-11, Norrlands Universitetssjukhus, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-01-27 Skapad: 2017-01-23 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
2. Hidden patterns that matter: statistical methods for analysis of DNA and RNA data
Öppna denna publikation i ny flik eller fönster >>Hidden patterns that matter: statistical methods for analysis of DNA and RNA data
2020 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Dolda betydelsefulla mönster : statistiska metoder för analys av DNA och RNA data
Abstract [en]

Understanding how the genetic variations can affect characteristics and function of organisms can help researchers and medical doctors to detect genetic alterations that cause disease and reveal genes that causes antibiotic resistance. The opportunities and progress associated with such data come however with challenges related to statistical analysis. It is only by using properly designed and employed tools, that we can extract the information about hidden patterns. In this thesis we present three types of such analysis. First, the genetic variant in the gene COL17A1 that causes corneal dystrophy with recurrent erosions is reveled. By studying Next-generation sequencing data, the order of the nucleotides in the DNAsequence was be obtained, which enabled us to detect interesting variants in the genome. Further, we present results of an experimental design study with the aim to make the best selection from a family that is affected by an inherited disease. In second part of the work, we analyzed a novel antibiotic resistance Staphylococcus epidermidis clone that is only found in northern Europe. By investigating its genetic data, we revealed similarities to a world known antibiotic resistance clone. As a result, the antibiotic resistance profile is established from the DNA sequences. Finally, we also focus on the challenges related to the abundance of genetic data from different sources. The increasing number of public gene expression datasets gives us opportunity to increase our understanding by using information from multiple sources simultaneously. Naturally, this requires merging independent datasets together. However, when doing so, the technical and biological variation in the joined data increases. We present a pre-processing method to construct gene co-expression networks from a large diverse gene-expression dataset.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, Institutionen för matematik och matematisk statistik, 2020. s. 26
Serie
Research report in mathematical statistics, ISSN 1653-0829 ; 71/20
Nyckelord
Genome, Next-generation sequence, statistics, microarrays, bacteria, antibiotic resistance, inherited diseases, Co-expression networks, centralization within subgroups
Nationell ämneskategori
Sannolikhetsteori och statistik Biologiska vetenskaper Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:umu:diva-175242 (URN)978-91-7855-240-5 (ISBN)978-91-7855-241-2 (ISBN)
Disputation
2020-10-16, Hörsal B, Lindellhallen, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2020-09-25 Skapad: 2020-09-22 Senast uppdaterad: 2020-09-23Bibliografiskt granskad

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Jonsson, FridaByström, BeritBackman, Ludvig J.Kellgren, ThereseRyden, PatrikSandgren, OlaDanielson, PatrikGolovleva, Irina

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Jonsson, FridaByström, BeritBackman, Ludvig J.Kellgren, ThereseRyden, PatrikSandgren, OlaDanielson, PatrikGolovleva, Irina
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Medicinsk och klinisk genetikOftalmiatrikAnatomiInstitutionen för matematik och matematisk statistik
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