ABCA4 modeled structure provides a molecular basis on which to analyze protein sequence mutations related to genetic retinal disease in order to predict the risk of retinal disease across all possible ABCA4 mutations.
A commercial diagnostic array-based assay has been developed targeting known mutations, however a conclusive genetic diagnosis must rely on a comprehensive genetic screening as the mutation spectrum of ABCA4-related retinopathies continues to expand.
Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease?
Based on recent studies of the photoreceptor-specific ABC transporter gene ABCR (ABCA4) in Stargardt disease (STGD1) and other retinal dystrophies, we and others have developed a model in which the severity of retinal disease correlates inversely with residual ABCR activity.
Based on these data we estimate a prevalence of 31% for ABCA4 mutations in arCD and arCRD, supporting the concept that the ABCA4 gene is a major locus for various types of degenerative retinal diseases with abnormalities in cone or both cone and rod function.
Disease in 11 patients was explained by mutations outside ABCA4, underlining the need to genotype all retinal disease genes to maximize genetic diagnostic rates.
Eighteen affected individuals from 13 families ascertained from a total cohort of 214 families with ABCA4-related retinal disease presenting to a single center.
Four novel pathogenic variants, p.Gln636Lys, p.Ile1114del, p.Thr1117Ala, and p.Asn1588Tyr, were identified. p.Gln294Ter, p.Leu1157Ter, and p.Lys2049ArgfsTer12 were repeatedly detected in Koreans with <i>ABCA4</i>-associated retinal diseases (<i>ABCA4-</i>RD).
Identification of ABCA4retinopathies provides a specific molecular diagnosis and justifies a prompt introduction of simple precautions that may slow disease progression.
In a further 5.9% of patients (n = 5), a single heterozygous ABCA4 variant was identified; all these participants had a spectrum of clinical features consistent with ABCA4retinopathy.
In contrast, we report a statistically significant association of common variants in the ABCA4 gene with retinal disease, assessed by a score-based variance-component test (PSKAT = 0.0055).
In-depth knowledge of the ABCR mutation spectrum in patients with Stargardt disease will provide for more efficient screening and may provide potential therapies for Stargardt disease and other retinal diseases.
Initial testing involved eight patients with central retinal disease (Stargardt disease, STGD) and eight with peripheral retinal disease (retinitis pigmentosa, RP), who were examined using fMRI and MP (Nidek MP-1).