1,721,072 research outputs found
Gene Therapy of ABCA4-Associated Diseases.
No full textThe ATP-binding cassette (ABC) transporter gene, ABCA4 (ABCR), was characterized in 1997 as the causal gene for autosomal recessive Stargardt disease (STGD1). Shortly thereafter several other phenotypes were associated with mutations in ABCA4, which now have collectively emerged as the most frequent cause of retinal degeneration phenotypes of Mendelian inheritance. ABCA4 functions as an important transporter (or "flippase") of vitamin A derivatives in the visual cycle. Several ways to alleviate the effects of the defective ABCA4 protein, which cause accumulation of 11-c/s and all-trans-retinal in photoreceptors and lipofuscin in the retinal pigment epithelium, have been proposed. Although ABCA4 has proven to be a difficult research target, substantial progress through genetic, functional, and translational studies has allowed major advances in therapeutic applications for ABCA4-associated pathology, which should be available to patients in the (near) future. Here, we summarize the status of the gene therapy-based treatment options of ABCA4-associated diseases. © 2015 Cold Spring Harbor Laboratory Press; all rights reserved
Pseudo-vitelliform macular detachment and cuticular drusen: Exclusion of 6 candidate genes
No full textPurpose: The etiology and genetic cause of pseudo-vitelliform macular detachment with cuticular drusen (PVMD/CD) are unknown; nor is it clear if this phenotype represents a separate disease entity, or is a sub-phenotype of disorders with overlapping clinical presentation. To answer this question, we screened a cohort of patients affected with PVMD/CD for variation in six plausible candidate genes (ABCA4, VMD2, TIMP-3, peripherin/RDS, fibulin 5 (FIBL5) and complement factor H (CFH)) associated with diseases of overlapping phenotypes. Methods: Twenty-eight patients, diagnosed with pseudo-vitelliform macular detachment and cuticular drusen, were evaluated by clinical examination, fundus photography, fluorescein angiography and autofluorescence imaging. DNA from all study subjects were screened for variants in the ABCA4, VMD2, TIMP-3, peripherin/RDS, FIBL5 and CFH genes by a combination of DHPLC, array screening and direct sequencing. Results: All patients presented with cuticular drusen; pseudo-vitelliform detachment was seen in 21 cases, while atrophic changes following regression of the detachment were seen in the remaining 7 subjects. Visual acuity ranged from 20/20 to CF. The screening revealed an I32V mutation in peripherin/RDS in one patient and 2ABCA4 variants, T897I and G1961E, in 2 more patients. No amino acid-altering variants were detected in VMD2, TIMP-3, and FIBL5 genes. The frequency of the CFH Y402H variant in this cohort corresponded to that detected in the general population. Conclusions: Screening of 6 candidate genes detected possibly disease-associated mutations in only 3/28 (10.7%) of patients presenting with PVMD/CD, eliminating these genes as causal for this phenotype. Copyright © Informa Healthcare USA, Inc
Clinical expression of cone dystrophy associated with a novel deleterious ABCR (ABCA4) mutation in an italian family
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Genotype-phenotype correlation in Italian families with Stargardt disease
No full textAutosomal recessive Stargardt disease (STGD) has been associated with substantial genetic and phenotypic heterogeneity. By systematic clinical analyses of STGD patients with complete genetic data (i.e. identified mutations on both alleles of the ABCA4 gene), we set out to determine phenotypic subtypes and to correlate these with specific ABCA4 alleles. Twenty-eight patients from 18 families with STGD/fundus flavimaculatus were investigated. All patients were submitted to complete ophthalmologic examination, electrophysiology, fluorescein angiography and ABCA4 gene chip analysis. Two main clinical phenotypes were observed among the examined patients. The severe phenotype was characterized by the onset of the disease <20 years and reduced ERG response, whereas the mild phenotype presented with later onset of the disease and a normal ERG response. Genetic analysis of the ABCA4 gene revealed, in the severe group, more frequently deletions, stop codons and insertions as compared to the mild phenotype group (p = 0.0113 by Fisher's exact test). Moreover, the compound heterozygous mutations G1961E/5018 + 2T → C found in 7 patients from 3 unrelated STGD families were associated with a mild phenotype in all subjects, except 1. This study documented variability of the clinical expression of STGD in relation to the age of onset of the disease, fundus appearance and the ERG response and allowed to subdivide patients into a severe and a mild phenotype group. These findings suggest that an extensive and comprehensive genetic analysis of STGD patients combined with thorough clinical evaluation, including the careful recording of the age of onset of the disease, would allow a more precise prognostic evaluation. Copyright © 2005 S. Karger AG
Clinical expression of cone dystrophy associated with a novel deleterious ABCR (ABCA4) mutation in an italian family
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