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.

Figure 1

Fundus appearance in four patients with CRD. a, Patient 11872, with perifoveal atrophy of the retinal pigment epithelium (RPE) (bull's eye) and atrophy of the RPE outside the macula. b, Patient 9633, with pericentral atrophy of the RPE. Arteries are slightly attenuated. c, Patient 9378, with central hypo- and hyperpigmentation, patchy atrophy of the RPE temporal to the macula, normal vessels, and normal optic disk. d, Patient 9369, with atrophy of the RPE around the optic disk, bone spicules along arteries and venules in the midperiphery, and attenuated arterioles. The periphery of the retina is normal. Patients 9378 (c) and 9369 (d) were classified as atypical.

Figure 2

DNA sequences in patients carrying the complex ABCA4 allele L541P;A1038V. a–b, Normal nucleotide sequences of exon 12 (a) and exon 21 (b) in a control individual. c–d, Heterozygous 1622T→C (c) and 3113C→T (d) nucleotide changes in patient 9370. e–f, Homozygous 1622T→C (e) and 3113C→T (f) nucleotide changes in patient 9371.

Figure 3

Genotype-phenotype–correlation model and estimated incidence of ABCA4 mutations in patients with retinal dystrophies (adapted from work by van Driel et al. [1998]). The model shows the inverse correlation between the ABCA4 residual activity and the severity of the retinal dystrophy. The most severe phenotype, RP, is caused by two null/severe ABCA4 mutations. If the ABCA4 activity is partially retained, patients will develop either CRD, as the result of a severe mutation inherited together with a moderate mutation, or STGD1, as the result of a combination of a severe and a mild ABCA4 mutation.