Mutations in the ABCA4 (ABCR) Gene Are the Major Cause of Autosomal Recessive Cone-Rod Dystrophy

Abstract

The photoreceptor cell-specific ATP-binding cassette transporter gene (ABCA4; previously denoted "ABCR") is mutated, in most patients, with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients from Germany and The Netherlands with isolated CRD. Single-strand conformation-polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans.

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

“…21 In the same way as for the LCArelated genes, mutations in ABCA4 cause not only STGD1 but also cone-rod dystrophy and RP. 22,23 Molecular genetic testing is desirable for facilitating the diagnosis of LCA, early-onset RP and STGD1. This study was conducted to investigate the genetic defects in a Swedish family that manifests two distinct retinal degenerations: STGD1 and LCA.…”

Retinoid Binding Properties of Nucleotide Binding Domain 1 of the Stargardt Disease-associated ATP Binding Cassette (ABC) Transporter, ABCA4

“…The retina-specific ABC 2 transporter, ABCA4 protein, has been linked through genetic studies to a number of inherited visual diseases, including Stargardt macular dystrophy (1,2), fundus flavimaculatus (3)(4)(5)(6), autosomal recessive retinitis pigmentosa (6 -11), cone-rod dystrophy (8,(12)(13)(14)(15)(16)(17), and perhaps increased susceptibility to age-related macular degeneration (1,2,12,18,19). Stargardt disease and its adult onset variant, fundus flavimaculatus, are autosomal recessive disorders affecting ϳ1 in 10,000 in the population.…”

Three different ABCA4 mutations in the same large family with several consanguineous loops affected with autosomal recessive cone–rod dystrophy

“…3,4 In addition, it is admitted that the frequency of carriers of ABCA4 mutations in the general population ranges from 1/20 to 1/10. 7 -9 In light of these data, we made the hypothesis of the localization of the disease-causing gene in this inbred family at the CORD3 locus despite the absence of homozygosity for all patients.…”

“…Indeed, mutations in this retinal-specific ATPbinding cassette gene account for all cases of early-and late-onset autosomal recessive Stargardt disease (arSTGD; MIM 248200) and for the main part of autosomal recessive cone -rod dystrophies (arCRDs). 3,4 Some mutations in ABCA4 have been reported in exceptional cases of retinitis pigmentosa (RP). 5,6 A substantial allelic heterogeneity has been described (Human Gene Mutation Database).…”