One possible molecular explanation to the different clinical expressions may be the T972N substitution present in the ABCR protein in one of the STGD1 families investigated.
These findings support the hypothesis that compound heterozygous ABCR mutations are responsible for STGD1 and that some heterozygous ABCR mutations may enhance susceptibility to AMD.
We have studied 144 patients with STGD and 220 unaffected individuals ascertained from the German population, to complete a comprehensive, population-specific survey of the sequence variation in the ABCA4 gene.
In addition, we report three new pseudodominant families that now comprise eight of 178 outbred STGD1 families and suggest a carrier frequency of STGD1-associated ABCR mutations of about 4.5% (approximately 1/22).
Clinical evaluation of these families affected by STGD1 showed an unusually high frequency of early age-related macular degeneration (AMD) in parents of patients with STGD1 (8/22; 36%), consistent with the hypothesis that some heterozygous ABCR mutations enhance susceptibility to AMD.
Fifty-six patients exhibiting the STGD/FFM phenotype, 6 with arRP, and 8 with arCRD, were screened for mutations in the 50 exons of the ABCR gene by heteroduplex analysis and direct sequencing.
Complete exon-intron structure of the retina-specific ATP binding transporter gene (ABCR) allows the identification of novel mutations underlying Stargardt disease.
Here, we report on the screening of the whole coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM families and we show that mutations truncating the ABCR protein consistently led to STGD.
Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype.
In order to further characterize the complex genotype-phenotype relationships involving this gene, we have performed a mutation analysis of ABCA4 in 14 Spanish patients comprising eight STGD (Stargardt), four FFM (fundus flavimaculatus), and two CRD (Cone-rod dystrophy) patients.