暂无摘要。

The ABCA4 gene encodes an ATP-binding cassette transporter that is expressed specifically in the disc of photoreceptor outer segments. Mutations in the ABCA4 gene are the main cause of retinal degenerations known as \"ABCA4-retinopathies.\" Recent research has revealed that ABCA4 is expressed in other cells as well, such as hair follicles and keratinocytes, although no information on its significance has been evidenced so far. In this study, we investigated the role of the ABCA4 gene in human keratinocytes and hair follicle stem cells for the first time. We have shown that silencing the ABCA4 gene increases the deleterious effect of all-trans-retinal on human hair follicle stem cells.

Inherited retinal dystrophies comprise a broad group of genetic eye diseases without effective treatment. Among them, Stargardt disease is the second most prevalent pathology. This pathology triggers progressive retinal degeneration and vision loss in children and adults. In recent years, the evolution of several genome editing technologies, such as the CRISPR-Cas9 system, has revolutionized disease modeling and personalized medicine. Human induced pluripotent stem cells also provide a valuable tool for in vitro disease studies and therapeutic applications. Here, we show precise correction of two ABCA4 pathogenic variants in human induced pluripotent stem cells from two unrelated patients affected with Stargardt disease. Gene editing was achieved with no detectable off-target genomic alterations, demonstrating efficient ABCA4 gene correction without deleterious effects. These results will contribute to the development of emerging gene and cell therapies for inherited retinal dystrophies.

The aim of the present study is to determine how electroretinographic (ERG) responses reflect age-related disease progression in the Stargardt disease (STGD1). The prospective comparative cohort study included 8 patients harboring two null ABCA4 variants (Group 1) and 34 patients with other ABCA4 genotypes (Group 2). Age at exam, age at onset, visual acuity (VA) and ERG responses were evaluated. The correlation between ERG responses and age in each patient group was determined using linear regression. A Mann-Whitney U Test was used to compare the median values between the groups. Age of onset was significantly earlier in Group 1 than in Group 2 (8 vs. 18), while disease duration was similar (13 vs. 12 years, i.e., advanced stage). Group 1 had significantly worse VA and lower ERG responses. ERG responses that significantly correlated with age in Group 1 were DA 0.01 and 3.0 ERG, which represented a retinal rod system response. The only ERG response that significantly correlated with age in Group 2 was the S-cone ERG. The observed difference was likely due to early cone loss occurring in double-null patients and slower photoreceptor loss in patients with other genotypes. The results suggest that specific ERG responses may be used to detect double-null patients at an early stage and monitor STGD1 disease progression in patients with specific genotypes.

UNASSIGNED: To report on a patient with Stargardt disease (STGD1) and with an intronic mutation in the ABCA4 gene.
UNASSIGNED: A 69-year-old female patient presented to the clinic complaining of progressive vision loss. The ophthalmic evaluation was remarkable for a best corrected visual acuity of counting fingers at 5\' in the right eye and 3\' in the left eye. Imaging revealed deep extensive atrophy of the central macula, epithelial pigment hyperplasia, and other areas of multifocal atrophy in the right eye. Furthermore, fundus autofluorescence imaging of the macula showed central hypoautofluorescence with bilateral expansion to the periphery in both eyes. A full-field electroretinogram showed a normal rod response, with decreased cone response, bilaterally. Genetic testing was positive for a homozygous intronic mutation in the ABCA4 gene of the variant c.5714+5G>A.
UNASSIGNED: Patients with STGD1 due to presumed mild or moderate mutations in the ABCA4 gene may have a more severe presentation and progression of the disease. Based on this, the first report of a genotype-phenotype correlation in a Puerto Rican patient with STGD1 disease, genotyping all Puerto Rican patients is warranted.

Inherited retinal diseases (IRDs) represent a spectrum of clinically and genetically heterogeneous disorders. Our study describes an IRD patient carrying ABCA4 and USH2A pathogenic biallelic mutations as a result of paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-year-old girl born from non-consanguineous parents. Both parents were asymptomatic and denied family history of ocular disease. Clinical history and ophthalmologic examination of the proband were consistent with Stargardt disease. Whispered voice testing disclosed moderate hearing loss. Next-generation sequencing and Sanger sequencing identified pathogenic variants in ABCA4 (c.4926C>G and c.5044_5058del) and USH2A (c.2276G>T). All variants were present homozygously in DNA from the proband and heterozygously in DNA from the father. No variants were found in maternal DNA. Further analysis of single nucleotide polymorphisms confirmed paternal UPD of chromosome 1. This is the first known patient with confirmed UPD for two recessively mutated IRD genes. Our study expands on the genetic heterogeneity of IRDs and highlights the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents. Moreover, a long-term follow-up is essential for the identification of retinal features that may develop as a result of USH2A-related conditions.

OBJECTIVE: To report a case of late-onset Stargardt disease, discuss the differential diagnosis, and review the role of vitamin A supplementation in Stargardt disease.
METHODS: A 60-year-old man presented with blurry vision in the right eye for the past two years. Current medications included a daily multivitamin containing vitamin A and age-related eye disease study vitamins. Examination revealed bilateral macular atrophy and scattered yellow flecks which were intensely hyperautofluorescent. Fluorescein angiography revealed a dark choroid. Full-field electroretinogram showed normal rod and cone responses, and genetic testing revealed two pathogenic ABCA4 gene variations confirming the diagnosis of late-onset Stargardt disease.
CONCLUSIONS: Stargardt disease is typically described in young patients but may develop later in adulthood and masquerade as age-related macular degeneration and a number of other conditions. Though the evidence is limited, there is concern that high-dose vitamin A supplementation could lead to progression of Stargardt disease. Avoidance of high-dose vitamin A supplementation should be discussed with Stargardt disease patients.

The clinical and genetic characteristics of ABCA4-associated inherited retinal diseases have been studied for more than 2 decades, since the identification of the ABCA4 protein in 1978 and the ABCA4 gene in 1997. ABCA4 mutations were initially associated with autosomal recessive Stargardt disease (STGD1). It has now been established that mutations in this gene can cause other inherited retinal diseases, such as cone-rod dystrophy and retinitis pigmentosa. In addition, the phenotypes of ABCA4-associated diseases can vary greatly from the classic presentation of Stargardt disease, from loss of central vision in adolescence to disease with early onset and rapid progression or late onset and milder course. ABCA4-associated diseases are inherited in autosomal recessive manner, i.e. the disease develops only if both alleles of the gene are damaged, one inherited from the father and the other inherited from the mother. As with many other recessive hereditary diseases, which are characterized by a variety of clinical manifestations, the diversity of the phenotypes of ABCA4-associated retinal diseases is explained by combinations of sequence variants in the ABCA4 gene inherited by patients from their parents. Despite the fact that in this respect inherited retinal diseases associated with mutations in the ABCA4 gene do not fundamentally differ from other autosomal recessive traits, due to the structure of the gene and the protein encoded by it, there are a number of features thatshould be taken into account when performing molecular diagnostics, predicting the possibility of manifestation and the course of the disease, and planning the approaches to treatment.
Изучение клинико-генетических характеристик наследственных заболеваний сетчатки (НЗС) при мутациях гена АВСА4 уже на протяжении более двух десятилетий остается актуальной темой, с тех пор как в 1978 г. был идентифицирован белок АВСА4, а в 1997 г. — ген АВСА4, мутации которого вначале были ассоциированы с аутосомно-рецессивной болезнью Штаргардта (БШ, STGD1). В настоящее время установлено, что мутации этого гена могут быть причиной других НЗС: палочко-колбочковой дистрофии (ПКД), пигментного ретинита (ПР). Кроме того, фенотип АВСА4-ассоциированных заболеваний может сильно варьировать от классической БШ с потерей центрального зрения в подростковом возрасте до заболевания с ранним началом и быстрым прогрессированием или с поздним началом и более легким течением. АВСА4-ассоциированные заболевания наследуются аутосомно-рецессивно, т.е. болезнь развивается только при условии повреждения обоих аллелей гена — одного, унаследованного от отца, и другого, унаследованного от матери. Как и при многих других рецессивных заболеваниях, для которых характерно разнообразие клинических проявлений, многообразие фенотипов АВСА4-ассоциированных заболеваний сетчатки объясняют комбинациями вариантов нуклеотидной последовательности в гене ABCA4, унаследованных пациентами от родителей. Несмотря на то что в этом отношении наследственные заболевания сетчатки, ассоциированные с мутациями гена ABCA4, принципиально не отличаются от других аутосомно-рецессивных заболеваний, существует ряд особенностей, обусловленных структурой гена и кодируемого им белка, которые необходимо учитывать при осуществлении молекулярной диагностики, прогнозировании возможности манифестации и характера течения заболевания и при планировании подходов к лечению.

Stargardt disease (STGD) is the most common form of juvenile macular dystrophy associated with progressive central vision loss, and is agenetically and clinically heterogeneous disease. Molecular diagnosis is of great significance in aiding the clinical diagnosis, helping to determine the phenotypic severity and visual prognosis. In the present study, we determined the clinical and genetic features of seven childhood-onset and three adult-onset Chinese STGD families. We performed capture next-generation sequencing (NGS) of the probands and searched for potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes.
In all, ten unrelated Chinese families were enrolled. Panel-based NGS was performed to identify potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes, including the five known STGD genes (ABCA4, PROM1, PRPH2, VMD2, and ELOVL4). Variant analysis, Sanger validation, and segregation tests were utilized to validate the disease-causing mutations in these families.
Using systematic data analysis with an established bioinformatics pipeline and segregation analysis, 17 pathogenic mutations in ABCA4 were identified in the 10 STGD families. Four of these mutations were novel: c.371delG, c.681T > G, c.5509C > T, and EX37del. Childhood-onset STGD was associated with severe visual loss, generalized retinal dysfunction and was due to more severe variants in ABCA4 than those found in adult-onset disease.
We expand the existing spectrum of STGD and reveal the genotype-phenotype relationships of the ABCA4 mutations in Chinese patients. Childhood-onset STGD lies at the severe end of the spectrum of ABCA4-associated retinal phenotypes.

UNASSIGNED: To describe the clinical and molecular spectrum of Stargardt disease (STGD) in a cohort of Argentinean patients.
UNASSIGNED: This retrospective study included 132 subjects comprising 95 probands clinically diagnosed with STGD and relatives from 16 of them. Targeted next-generation sequencing of the coding and splicing regions of ABCA4 and other phenocopying genes (ELOVL4, PROM1, and CNGB3) was performed in 97 STGD patients.
UNASSIGNED: We found two or more disease-causing variants in the ABCA4 gene in 69/95 (73%) probands, a single ABCA4 variant in 9/95 (9.5%) probands, and no ABCA4 variants in 17/95 (18%) probands. The final analysis identified 173 variants in ABCA4. Seventy-nine ABCA4 variants were unique, of which nine were novel. No significant findings were seen in the other evaluated genes.
UNASSIGNED: This study describes the phenotypic and genetic features of STGD1 in an Argentinean cohort. The mutations p.(Gly1961Glu) and p.(Arg1129Leu) were the most frequent, representing almost 20% of the mutated alleles. We also expanded the ABCA4 mutational spectrum with nine novel disease-causing variants, of which eight might be associated with South American natives.