The 2588G→C Mutation in the ABCR Gene Is a Mild Frequent Founder Mutation in the Western European Population and Allows the Classification of ABCR Mutations in Patients with Stargardt Disease

Abstract

In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. 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.

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

“…36 In our study, this variant was detected in almost 14% of the healthy controls, which is higher compared with the maximal frequency of 7.5% reported in a Finnish population in the 1000 Genomes project. 36 It is worth mentioning that ABCA4 c.2588G4C (p.G863A), the most frequent autosomal recessive mutation in the European population, is disease causative only in combination with a severe ABCA4 mutation, 32 and does not result in a STGD1 phenotype when present bi-allelic or in combination with a mild ABCA4 mutation. Maugeri et al 32 hypothesised the possibility of a carrier advantage due to the high carrier frequency of the 2588C allele in Sweden (1 out of 18), 37 although the incidence of STGD1 is not higher in our country than in the rest of Europe.…”

Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8

“…Although the frequency of nonsynonymous SNPs was a very small part of the total SNP counts (2.8%), the SNPs would likely influence protein function. By comparing our data with reports from elsewhere (Maugeri et al 1999;Dvorakova et al 2001;Hubacek et al 2001;Lee et al 2001;Lu et al 2001) and the SNPs deposited in the dbSNP database at the National Center for Biotechnology Information, we were able to consider 491 of the 605 SNPs (81%) to be novel (Tables 1 and 2). In addition, the overall frequencies of nucleotide substitutions were counted as 40% for A/G, 33.9% for C/T, 8.6% for A/C, 8.1% for C/G, 6.1% for G/T, and 3.3% for T/A (Table 3).…”

Clinical Utility Gene Card for: autosomal recessive cone-rod dystrophy

“…Large gene rearrangements are rare; three deletions in ABCA4 have been identified spanning exon 5, 18 and exon 20-22, respectively. [1][2][3] In the KCNV2 gene, several deletions are described ranging from single basepairs deletions to complete gene deletions. 4,5…”