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Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
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2013 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 11, 1266-1271 p.Article in journal (Refereed) Published
Abstract [en]

This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

Place, publisher, year, edition, pages
Nature Publishing Group, 2013. Vol. 21, no 11, 1266-1271 p.
Keyword [en]
CRB1, ABCA4, SNP-array, Stargardt disease, Leber congenital amaurosis
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-82275DOI: 10.1038/ejhg.2013.23ISI: 000325861500015PubMedID: 23443024OAI: oai:DiVA.org:umu-82275DiVA: diva2:660357
Available from: 2013-10-29 Created: 2013-10-29 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Underlying genetic mechanisms of hereditary dystrophies in retina and cornea
Open this publication in new window or tab >>Underlying genetic mechanisms of hereditary dystrophies in retina and cornea
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2017. 57 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1872
Keyword
Cornea, retina, gene, mutation detection, inherited diseases
National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-130538 (URN)978-91-7601-626-8 (ISBN)
Public defence
2017-02-17, Major Groove, Målpunkt J-11, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
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Available from: 2017-01-27 Created: 2017-01-23 Last updated: 2017-02-01Bibliographically approved

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