Abca4

Adenine base editors (ABEs) are precise gene-editing agents that convert A:T pairs into G:C through a deoxyinosine intermediate. Existing ABEs function most effectively when the target A is in a TA context. Here we evolve the Escherichia coli transfer RNA-specific adenosine deaminase (TadA) to generate TadA8r, which extends potent deoxyadenosine deamination to RA (R = A or G) and is faster in processing GA than TadA8.20 and TadA8e, the two most active TadA variants reported so far. ABE8r, comprising TadA8r and a Streptococcus pyogenes Cas9 nickase, expands the editing window at the protospacer adjacent motif-distal end and outperforms ABE7...

INTRODUCTION: Mutational screening of inherited retinal disorders is prerequisite for gene targeted therapy. Our aim is to report and analyze the proportions of mutations in inherited retinal disease (IRD) causing genes from a single center in Switzerland in order to describe the distribution of IRDs in Western Switzerland. METHODS: We conducted a retrospective study of patient records. Criteria for inclusion were residence in Western Switzerland for patients and relatives presenting a clinical diagnosis of IRDs and an established molecular diagnosis managed by the genetics service of the Jules-Gonin Eye Hospital (JGEH) of Lausanne between January 2002 and December 2022...

(1) Purpose: ABCA4 -associated retinal degeneration ( ABCA4 -RD) is a phenotypically diverse disease that often evades diagnosis, even by experienced retinal specialists. This may lead to inappropriate management, delayed genetic testing, or inaccurate interpretation of genetic testing results. Here, we illustrate the phenotypic diversity of ABCA4 -RD using a series of representative cases and compare these to other conditions that closely mimic ABCA4 -RD. (2) Methods: Genetically confirmed ABCA4 -RD cases with representative phenotypes were selected from an inherited retinal disease cohort in Singapore and compared to phenocopies involving other retinal diseases...

Mutations in many visual cycle enzymes in photoreceptors and retinal pigment epithelium (RPE) cells can lead to the chronic accumulation of toxic retinoid byproducts, which poison photoreceptors and the underlying RPE if left unchecked. Without a functional ATP-binding cassette, sub-family A, member 4 (ABCA4), there is an elevation of all- trans -retinal and prolonged buildup of all- trans -retinal adducts, resulting in a retinal degenerative disease known as Stargardt-1 disease. Even in this monogenic disorder, there is significant heterogeneity in the time to onset of symptoms among patients...

Inherited retinal diseases (IRDs) constitute a prevalent group of inherited ocular disorders characterized by marked genetic diversity alongside moderate clinical variability. Among these, ABCA4 -related eye pathology stands as a prominent form affecting the retina. In this study, we conducted an in-depth analysis of 96 patients harboring ABCA4 variants in the European part of Russia. Notably, the complex allele c.[1622T>C;3113C>T] (p.Leu541Pro;Ala1038Val, or L541P;A1038V) and the variant c.5882G>A (p...

Pathogenic variants in ABCA4 are associated with Stargardt disease (STGD1), an autosomal recessive macular dystrophy characterized by bilateral central vision loss due to a progressive degeneration of retinal cells. An induced pluripotent stem cell (iPSC) line was generated from late-onset STGD1 patient-derived fibroblasts harboring bi-allelic ABCA4 variants by lentivirus-induced reprogramming. The obtained iPSC line (RMCGENi020-A) showed pluripotent features after the reprogramming process. The generation of this iPSC line facilitates its use to differentiate it into relevant retinal-like cell models, with the aim to adequately evaluate the effects of the ABCA4 variants...

BACKGROUND: The most prevalent cyanotic congenital heart disease (CHD) phenotype is tetralogy of Fallot (TOF). Rare genetic variations have been identified as significant risk factors for CHD. Thus, this research sought to identify the pathogenic variations and molecular etiologies of TOF. METHODS: This study employed whole-exome sequencing (WES) and Sanger sequencing to identify pathogenic variations in DNA samples from patients with TOF. The pathogenicity of the variations was predicted using an in-silico approach...

Stargardt macular dystrophy (Stargardt disease; STGD1; OMIM 248200) is the most prevalent inherited macular dystrophy. STGD1 is an autosomal recessive disorder caused by multiple pathogenic sequence variants in the large ABCA4 gene (OMIM 601691). Major advances in understanding both the clinical and molecular features, as well as the underlying pathophysiology, have culminated in many completed, ongoing and planned human clinical trials of novel therapies.The aims of this concise review are to describe (1) the detailed phenotypic and genotypic characteristics of the disease, multimodal imaging findings, natural history of the disease, and pathogenesis, (2) the multiple avenues of research and therapeutic intervention, including pharmacological, cellular therapies and diverse types of genetic therapies that have either been investigated or are under investigation and (3) the exciting novel therapeutic approaches on the translational horizon that aim to treat STGD1 by replacing the entire 6...

Mutations in ABCA4 are the most common cause of Mendelian retinal disease. Clinical evaluation of this gene is challenging because of its extreme allelic diversity, the large fraction of non-exomic mutations, and the wide range of associated disease. We used patient-derived retinal organoids as well as DNA samples and clinical data from a large cohort of patients with ABCA4-associated retinal disease to investigate the pathogenicity of a variant in ABCA4 (IVS30 + 1321 A > G) that occurs heterozygously in 2% of Europeans...

PURPOSE: To investigate the clinical and genotypic differences in the spectrum of ABCA4-associated retinopathies (ABCA4R). DESIGN: Observational, cross-sectional case series. PARTICIPANTS: Sixty-six patients (132 eyes) carrying biallelic ABCA4 variants. METHODS: Patients underwent visual acuity measurement and multimodal imaging. Clinical records were reviewed for age at onset, presenting symptoms, genetic variants, and electroretinogram (ERG)...

OBJECTIVE: To cluster the diverse phenotypic features of Stargardt disease (STGD) using unsupervised clustering of multimodal retinal structure and function data. DESIGN: Retrospective cross-sectional study. SUBJECTS: Eyes of subjects with STGD and fundus autofluorescence (FAF), OCT, electroretinography (ERG), and microperimetry (MP) data available within 1 year of the baseline evaluation. METHODS: A total of 46 variables from FAF, OCT, ERG, and MP results were recorded for subjects with STGD as defined per published criteria...

Large genes including several CRISPR-Cas modules like gene activators (CRISPRa) require dual adeno-associated viral (AAV) vectors for an efficient in vivo delivery and expression. Current dual AAV vector approaches have important limitations, e.g., low reconstitution efficiency, production of alien proteins, or low flexibility in split site selection. Here, we present a dual AAV vector technology based on reconstitution via mRNA trans-splicing (REVeRT). REVeRT is flexible in split site selection and can efficiently reconstitute different split genes in numerous in vitro models, in human organoids, and in vivo...

Autosomal recessive Stargardt disease (STGD1) is an inherited retinal degenerative disease associated with a mutated ATP-binding cassette, subfamily A, member 4 ( ABCA4 ) gene. STGD1 is the most common form of juvenile macular degeneration with onset in late childhood to early or middle adulthood and causes progressive, irreversible visual impairment and blindness. No effective treatment is currently available. In the present article, we review the most recent updates in clinical trials targeting the management of STGD1, including gene therapy, small molecule therapy, and stem cell therapy...

Introduction: Inherited retinal dystrophies (IRDs) can be caused by variants in more than 280 genes. The ATP-binding cassette transporter type A4 ( ABCA4 ) gene is one of these genes and has been linked to Stargardt disease type 1 (STGD1), fundus flavimaculatus, cone-rod dystrophy (CRD), and pan-retinal CRD. Approximately 25% of the reported ABCA4 variants affect RNA splicing. In most cases, it is necessary to perform a functional assay to determine the effect of these variants. Methods: Whole genome sequencing (WGS) was performed in one Spanish proband with Stargardt disease...

Adaptive optics (AO) imaging enables direct, objective assessments of retinal cells. Applications of AO show great promise in advancing our understanding of the etiology of inherited retinal disease (IRDs) and discovering new imaging biomarkers. This scoping review systematically identified and summarized clinical studies evaluating AO imaging in IRDs. Ovid MEDLINE and EMBASE were searched on 6 February 2023. Studies describing AO imaging in monogenic IRDs were included. Study screening and data extraction were performed by 2 reviewers independently...

PURPOSE: To depict the variant profiles of the ABCA4 gene in a large Chinese cohort of patients with ABCA4-associated retinal dystrophy (ABCA4-RD). METHODS: We recruited 290 unrelated Chinese patients with ABCA4-RD and did ABCA4 mutational screening by a combination of Sanger sequencing, targeted exome sequencing, entire ABCA4 locus sequencing, and whole genome sequencing (WGS). The pathogenicity of variants was assessed using in silico tools or in vitro splicing assays following the American College of Medical Genetics and Genomics guidelines...

60-year-old woman referring visual disability. She presented bone spicule pigmentation and retinal atrophy in all peripheral retina, as well as macular retinal flecks. Multimodal imaging showed typical findings of both inherited retinal dystrophies (IRD). Electroretinogram confirmed rod dysfunction. Biallelic mutations were found in ABCA4 and CNGA1 genes. Although not common, different IRDs may be present in a same patient at the same time. This is the first reported case of the combination of RP with late-onset Stargardt's disease...

PURPOSE: To determine the disease pathogenesis associated with the frequent ABCA4 variant c.5714+5G>A (p.[=,Glu1863Leufs*33]). METHODS: Patient-derived photoreceptor precursor cells were generated to analyze the effect of c.5714+5G>A on splicing and perform a quantitative analysis of c.5714+5G>A products. Patients with c.5714+5G>A in trans with a null allele (i.e., c.5714+5G>A patients; n = 7) were compared with patients with two null alleles (i.e...

The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrophy probands. A total of 858 probands were collected from 26 centers, of whom 722 carried no or one pathogenic ABCA4 variant while 136 cases carried two ABCA4 alleles, one of which was a frequent mild variant, suggesting that deep-intronic variants (DIVs) or other cis-modifiers might have been missed...

PURPOSE: To investigate the possible correlation factors of choroidal thickness in ABCA4 -related retinopathy. METHODS: A total of 66 patients were included in the cohort. It is a retrospective, cross-sectional laboratory investigation. The patients were tested using whole-exon sequencing and ophthalmic examinations, including slit-lamp examinations, best-corrected visual acuity, spectral-domain optical coherence tomography, fundus photograph, and fundus autofluorescence...