ABCA4-Associated Stargardt Disease

Khan, Mubeen; Cremers, Frans P.M.

doi:10.1055/a-1057-9939

Cited by 23 publications

(22 citation statements)

References 49 publications

(48 reference statements)

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“…Also, reverse transcription reactions are difficult to conduct on large genes where 5 of the gene may not be efficiently retrotranscribed, as compared with 3 of the gene. For this purpose, the construction of mini-or midigenes is more favorable, even though mini-genes may result in the creation of splicing artefacts [13]. In order to improve the accuracy of these assays, interesting results regarding functional analysis of the ABCA4 splice-site variants were obtained with photoreceptor precursor cells generated from skin fibroblasts [24,27,32,33].…”

Section: Discussionmentioning

confidence: 99%

“…According to the Human Gene Mutation Database (HGMD Professional version 2019.4), 1467 ABCA4 gene mutations have been identified so far, though novel, potentially pathogenic ABCA4 gene variants are still being detected. The ABCA4 gene carries a high number of non-canonical splice variants and protein-truncating mutations, which constitute the second highest type of genetic aberration, after missense mutations [12,13]. Residual activity of the mutant ABCA4 protein supposedly determines the severity of the disease [14].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

Ścieżyńska

Soszyńska

Komorowski

et al. 2020

IJMS

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ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the ABCA4 gene splice-site variants in patients with ABCA4 retinopathies. We assessed ABCA4 expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length ABCA4 transcripts and analyzed ABCA4 transcripts from three patients with Stargardt disease carrying different splice-site ABCA4 variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of ABCA4 variants in patients with ABCA4 retinopathies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

Ścieżyńska

Soszyńska

Komorowski

et al. 2020

IJMS

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“…Genotype-phenotype correlation in ABCA4 is generally thought to correlate with the remaining function of ABCA4, meaning that more severe combinations, such as having two null variants, results in a severe phenotype with an early disease onset whilst milder variants are linked with later onset [53][54][55]. In this review, we will describe the effects of these different variants and the up-to-date methods used to investigate a variant's severity.…”

Section: Function and Role Within The Visual Cyclementioning

confidence: 99%

An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

Al‐Khuzaei

Broadgate

Foster

et al. 2021

Genes

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Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner. The gene encodes an importer flippase protein that prevents the build-up of vitamin A derivatives that are toxic to the RPE. Diagnosing ABCA4R is complex due to its phenotypic variability and the presence of other inherited retinal dystrophy phenocopies. ABCA4 is a large gene, comprising 50 exons; to date >2000 variants have been described. These include missense, nonsense, splicing, structural, and deep intronic variants. Missense variants account for the majority of variants in ABCA4. However, in a significant proportion of patients with an ABCA4R phenotype, a second variant in ABCA4 is not identified. This could be due to the presence of yet unknown variants, or hypomorphic alleles being incorrectly classified as benign, or the possibility that the disease is caused by a variant in another gene. This underlines the importance of accurate genetic testing. The pathogenicity of novel variants can be predicted using in silico programs, but these rely on databases that are not ethnically diverse, thus highlighting the need for studies in differing populations. Functional studies in vitro are useful towards assessing protein function but do not directly measure the flippase activity. Obtaining an accurate molecular diagnosis is becoming increasingly more important as targeted therapeutic options become available; these include pharmacological, gene-based, and cell replacement-based therapies. The aim of this review is to provide an update on the current status of genotyping in ABCA4 and the status of the therapeutic approaches being investigated.

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“…High ABCA4 carrier frequencies are illustrated by common observations of pseudodominant inheritance, [10][11][12][13][14] and different combinations of disease-causing ABCA4 variants among siblings. 9,15 The large difference in the age of onset of STGD1 between patients is hypothesized to be mainly caused by the variable amount of residual ABCA4 activity. The combination of ABCA4 variants of different severity, ranging from null (severe) alleles, moderately severe alleles, to mild alleles, influences the clinical expression.…”

Section: Introductionmentioning

confidence: 99%

Genetic risk estimates for offspring of patients with Stargardt disease

Cornelis

Runhart

Bauwens

et al. 2021

Preprint

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BACKGROUND Genetic counseling in autosomal recessive Stargardt disease (STGD1) is complicated because of unknown frequencies of pathogenic ABCA4 alleles across populations, variable and unknown severity of ABCA4 alleles, and incomplete penetrance. METHODS In this cross-sectional study, published ABCA4 variants were categorized by severity based on previous functional and clinical studies and current statistical comparisons of their frequencies in patients versus the general population, their observed versus expected homozygous occurrence in patients, and their occurrence in combination with established mild alleles in patients. The sum allele frequencies of these severity categories were used to estimate inheritance risks for offspring of STGD1 patients and carriers of pathogenic ABCA4 variants. RESULTS The risk for offspring of a STGD1 patient with the severe|severe genotype or a severe|mild with complete penetrance genotype to develop STGD1 at some moment in life was estimated at 2.8-3.1% (1 in 35-32 individuals) and 1.6-1.8% (1 in 62-57 individuals), respectively. The risk to develop STGD1 in childhood was estimated to be 2 to 4-fold lower: 0.7-0.8% (1 in 148-124) and 0.3-0.4% (1 in 295-248), respectively. For offspring of an unaffected ABCA4 variant carrier from a STGD1 family who carries one severe or one mild ABCA4 variant with complete penetrance, the risk to develop STGD1 throughout life is 1.4-1.6% (1 in 71-64) and 0.19-0.21% (1 in 516-487), respectively. CONCLUSION We propose a genotype-based personalized counseling approach to appreciate the large differences in inheritance risk between individuals. We advocate considering the lower risk of early-onset STGD1 compared with the total STGD1 risk.

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ABCA4-Associated Stargardt Disease

Cited by 23 publications

References 49 publications

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

Genetic risk estimates for offspring of patients with Stargardt disease

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