ATP‐binding cassette subfamily A, member 4 intronic variants c.4773+3A&gt;G and c.5461‐10T&gt;C cause Stargardt disease due to defective splicing

Jönsson, Frida; Westin, Ida Maria; Österman, Lennart; Sandgren, Ola; Burstedt, Marie; Holmberg, Monica; Golovleva, Irina

doi:10.1111/aos.13676

Cited by 14 publications

(15 citation statements)

References 34 publications

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“…The most readily available method to assess variants involves use of plasmid transfection to recapitulate the patient’s mutation in mammalian cells. Minigene and Midigene constructs incorporating exons and introns for the IRD gene and including the candidate splice mutation have been hugely successful in providing empirical evidence of the functional effect of candidate splice variants [ 150 , 151 , 152 , 153 ]. Patient-derived cell and/or 3D retinal organoid models while more laborious to create, remove the need for transient expression of mutations as the mutation is already present in the patient’s cells.…”

Section: Modifiers Of Ird Phenotypesmentioning

confidence: 99%

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Dockery

Whelan

Humphries

et al. 2021

IJMS

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Inherited retinal diseases (IRDs) represent a collection of phenotypically and genetically diverse conditions. IRDs phenotype(s) can be isolated to the eye or can involve multiple tissues. These conditions are associated with diverse forms of inheritance, and variants within the same gene often can be associated with multiple distinct phenotypes. Such aspects of the IRDs highlight the difficulty met when establishing a genetic diagnosis in patients. Here we provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of IRD gene screening. These techniques have helped researchers globally to find elusive causes of IRDs, including copy number variants, structural variants, new IRD genes and deep intronic variants, among others. Resolving a genetic diagnosis with thorough testing enables a more accurate diagnosis and more informed prognosis and should also provide information on inheritance patterns which may be of particular interest to patients of a child-bearing age. Given that IRDs are heritable conditions, genetic counselling may be offered to help inform family planning, carrier testing and prenatal screening. Additionally, a verified genetic diagnosis may enable access to appropriate clinical trials or approved medications that may be available for the condition.

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Section: Modifiers Of Ird Phenotypesmentioning

confidence: 99%

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Dockery

Whelan

Humphries

et al. 2021

IJMS

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“…It was first discovered in 1999 in Stargardt disease patients (Maugeri et al, 1999), and has been described as the third most frequent gene variant associated with Stargardt disease in individuals with European or African descent (Zernant et al, 2011;Roberts et al, 2012;Miraldi Utz et al, 2014). Although it was initially identified as a sequence variant without significant functional consequence (Rivera et al, 2000), recent reports suggest that this mutation results in a decreased expression level of wild type ABCA4 and splicing defects with exons 39/40 skipped, leading to frameshift and premature stop, playing a causative and a pathological role in Stargardt disease (Sangermano et al, 2016;Aukrust et al, 2017;Jonsson et al, 2018). We predict that the intronic mutation, c.5461-10T > C in ABCA4, contributes to the Stargardt disease in Family 4100.…”

Section: Discussionmentioning

confidence: 99%

Mutation Screening in the miR-183/96/182 Cluster in Patients With Inherited Retinal Dystrophy

Coku

Muraleedharan

et al. 2020

Front. Cell Dev. Biol.

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Inherited retinal dystrophy (IRD) is a heterogenous blinding eye disease and affects more than 200,000 Americans and millions worldwide. By far, 270 protein-coding genes have been identified to cause IRD when defective. However, only one microRNA (miRNA), miR-204, has been reported to be responsible for IRD when a point-mutation occurs in its seed sequence. Previously, we identified that a conserved, polycistronic, paralogous miRNA cluster, the miR-183/96/182 cluster, is highly specifically expressed in all photoreceptors and other sensory organs; inactivation of this cluster in mice resulted in syndromic IRD with multi-sensory defects. We hypothesized that mutations in the miR-183/96/182 cluster in human cause IRD. To test this hypothesis, we perform mutation screening in the pre-miR-183, -96, -182 in >1000 peripheral blood DNA samples of patients with various forms of IRD. We identified six sequence variants, three in pre-miR-182 and three in pre-miR-96. These variants are in the pre-miRNA-182 or -96, but not in the mature miRNAs, and are unlikely to be the cause of the IRD in these patients. In spite of this, the nature and location of these sequence variants in the pre-miRNAs suggest that some may have impact on the biogenesis and maturation of miR-182 or miR-96 and potential roles in the susceptibility to diseases. Although reporting on negative results so far, our study established a system for mutation screening in the miR-183/96/182 cluster in human for a continued effort to unravel and provides deeper insight into the potential roles of miR-183/96/182 cluster in human diseases.

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“…Missense variants are usually caused by a single nucleotide change, which usually results in a change in the amino acid. The consequences of this are difficult to predict as not all amino acid changes lead to changes in the protein structure that result in a change in function [54,105,106]. Many of these missense variants are rare, which further complicates determining their severity and whether they are truly pathogenic [20,107,108].…”

Section: Spectrum Of Pathogenic Variants In Abca4mentioning

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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ATP‐binding cassette subfamily A, member 4 intronic variants c.4773+3A>G and c.5461‐10T>C cause Stargardt disease due to defective splicing

Cited by 14 publications

References 34 publications

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Next-Generation Sequencing Applications for Inherited Retinal Diseases

Mutation Screening in the miR-183/96/182 Cluster in Patients With Inherited Retinal Dystrophy

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

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