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ABCA4 intronic variants c.4773+3A and c.5461-10T>C cause Stargardt disease due to defective splicing.: Intronic ABCA4 variants cause splice defects in Stargardt disease
Umeå University, Faculty of Medicine, Department of Medical Biosciences. (Irina Golovleva)ORCID iD: 0000-0002-8899-2520
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Inherited retinal dystrophies (IRD) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRD and to-date more than 250 genes are associated with autosomal dominant, autosomal recessive and X-linked IRD. Stargardt disease (#248200) or macular degeneration with flecks, type 1, STGD1 is associated with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in ABCA4 gene. In this study, two intronic variants potentially causing the Stargardt disease were functionally tested in HEK293T and ARPE-19 cells using in vitro splice minigene assay. The two variants, c.4773+3A>G and c.5461-10T>C in the ABCA4 gene encoding ATP binding cassette sub-family A, member 4 protein, responsible for transport of a vitamin A precursor in the photoreceptors of the retina, were present in two Stargardt patients, members of the same Swedish family. It was suggested that the disease in one of the patients was caused by homozygous variant c.5461-10T>C and by both variants, in the other patient. The c.5461–10T>C, the third most common variant in STGD1 patients always segregating with the disease was proposed to be a polymorphism, a risk allele and finally, a disease-associated mutation, though its functional impact remained unknown for a long time. Functional analysis of the ABCA4 variants are complicated due to predominant expression of the ABCA4  in photoreceptors, which means no affected tissue can be easily obtained from the patients.

This study provides the evidence that c.4773+3A>G and c.5461-10T>C cause aberrant splicing and are indeed disease-causative variants.

National Category
Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:umu:diva-130535OAI: oai:DiVA.org:umu-130535DiVA: diva2:1067654
Available from: 2017-01-23 Created: 2017-01-23 Last updated: 2017-01-24
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)
Opponent
Supervisors
Available from: 2017-01-27 Created: 2017-01-23 Last updated: 2017-02-01Bibliographically approved

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