Evaluation of the common variants of the ABCA4 gene in families with Stargardt disease and autosomal recessive retinitis pigmentosa

Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in humans and dogs. Currently, no standard treatment is available but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs1395) was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium. The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.

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Stargardt Disease Caused by a Rare Combination of Double Homozygous Mutations

Medicina ◽

10.3390/medicina49080060 ◽

2013 ◽

Vol 49 (8) ◽

pp. 60

Author(s):

Danielius Serapinas ◽

Viltautė Obrikytė ◽

Raimundas Sakalauskas

Keyword(s):

Autosomal Recessive ◽

Severe Disease ◽

Disease Phenotype ◽

Stargardt Disease ◽

Recessive Mutations ◽

Rare Combination ◽

Abca4 Gene ◽

Genetic Mechanisms ◽

Blurry Vision ◽

Autosomal Recessive Pattern

Stargardt disease is a juvenile macular degeneration most often inherited in an autosomal recessive pattern, characterized by decreased vision in the first 2 decades of life. This report presents a clinical case of Stargardt disease: a 10-year-old female patient complained of blurry vision, and in a 4-year period, her visual acuity was reduced from OD=0.3 and OS=0.3 to OD=0.08 and OS=0.1, respectively. A genetic analysis revealed a rare combination of 2 homozygous recessive mutations in the ABCA4 gene, which caused Stargardt disease. The presence of different genetic mechanisms leading to a severe disease phenotype can challenge molecular geneticists, ophthalmologists, and genetic counselors.

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ABCA4-Associated Stargardt Disease

Klinische Monatsblätter für Augenheilkunde ◽

10.1055/a-1057-9939 ◽

2020 ◽

Vol 237 (03) ◽

pp. 267-274 ◽

Cited By ~ 1

Author(s):

Mubeen Khan ◽

Frans P.M. Cremers

Keyword(s):

Autosomal Recessive ◽

Late Onset ◽

Human Kidney ◽

In Vitro Assays ◽

Kidney Cells ◽

Stargardt Disease ◽

Abca4 Gene ◽

Transcriptomics Data ◽

Degree Of Severity

AbstractAutosomal recessive Stargardt disease (STGD1) is associated with variants in the ABCA4 gene. The phenotypes range from early-onset STGD1, that clinically resembles severe cone-rod dystrophy, to intermediate STGD1 and late-onset STGD1. These different phenotypes can be correlated with different combinations of ABCA4 variants which can be classified according to their degree of severity. A significant fraction of STGD1 cases, particularly late-onset STGD1 cases, were shown to carry only a single ABCA4 variant. A frequent coding variant (p.Asn1868Ile) was recently identified which – in combination with a severe ABCA4 variant – is generally associated with late-onset STGD1. In addition, an increasing number of rare deep-intronic variants have been found and some of these are also associated with late-onset STGD1. The effect of these and other variants on ABCA4 RNA was tested using in vitro assays in human kidney cells using specially designed midigenes. With stem cells and photoreceptor progenitor cells derived from patient skin or blood cells, retina-specific splice defects can be assessed. With expert clinical examination to distinguish STGD1 cases from other maculopathies, as well as in-depth genomics and transcriptomics data, it is now possible to identify both mutant ABCA4 alleles in > 95% of cases.

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Possible protective role of the ABCA4 gene c.1268A>G missense variant in Stargardt disease and syndromic retinitis pigmentosa in a Sicilian family: Preliminary data

International Journal of Molecular Medicine ◽

10.3892/ijmm.2017.2917 ◽

2017 ◽

Vol 39 (4) ◽

pp. 1011-1020 ◽

Cited By ~ 16

Author(s):

Rosalia D'Angelo ◽

Luigi Donato ◽

Isabella Venza ◽

Concetta Scimone ◽

Pasquale Aragona ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Preliminary Data ◽

Missense Variant ◽

Protective Role ◽

Stargardt Disease ◽

Abca4 Gene

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Faculty Opinions recommendation of EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1123361.580519 ◽

2008 ◽

Author(s):

Darryl Nishimura

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Recessive

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Antisense Oligonucleotide Screening to Optimize the Rescue of the Splicing Defect Caused by the Recurrent Deep-Intronic ABCA4 Variant c.4539+2001G>A in Stargardt Disease

Genes ◽

10.3390/genes10060452 ◽

2019 ◽

Vol 10 (6) ◽

pp. 452 ◽

Cited By ~ 9

Author(s):

Alejandro Garanto ◽

Lonneke Duijkers ◽

Tomasz Z. Tomkiewicz ◽

Rob W. J. Collin

Keyword(s):

Pluripotent Stem Cells ◽

Antisense Oligonucleotides ◽

Autosomal Recessive ◽

Stargardt Disease ◽

Single Nucleotide ◽

Significant Correction ◽

Nucleotide Mismatch ◽

Single Nucleotide Mismatch ◽

Splicing Defects ◽

Induced Pluripotent

Deep-sequencing of the ABCA4 locus has revealed that ~10% of autosomal recessive Stargardt disease (STGD1) cases are caused by deep-intronic mutations. One of the most recurrent deep-intronic variants in the Belgian and Dutch STGD1 population is the c.4539+2001G>A mutation. This variant introduces a 345-nt pseudoexon to the ABCA4 mRNA transcript in a retina-specific manner. Antisense oligonucleotides (AONs) are short sequences of RNA that can modulate splicing. In this work, we designed 26 different AONs to perform a thorough screening to identify the most effective AONs to correct splicing defects associated with c.4539+2001G>A. All AONs were tested in patient-derived induced pluripotent stem cells (iPSCs) that were differentiated to photoreceptor precursor cells (PPCs). AON efficacy was assessed through RNA analysis and was based on correction efficacy, and AONs were grouped and their properties assessed. We (a) identified nine AONs with significant correction efficacies (>50%), (b) confirmed that a single nucleotide mismatch was sufficient to significantly decrease AON efficacy, and (c) found potential correlations between efficacy and some of the parameters analyzed. Overall, our results show that AON-based splicing modulation holds great potential for treating Stargardt disease caused by splicing defects in ABCA4.

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