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

• DOI: 10.1086/302323
• Publication Date: 2002-07-26T14:47:41Z
• Authors: Alessandra Maugeri; Marc A. van Driel; Dorien J.R. van d...; B. Jeroen Klevering; Frank J.J. van Haren; Nel Tijmes; Arthur A.B. Bergen; Klaus Rohrschneider; Anita Blankenagel; Alfred J.L.G. Pin...; Niklas Dahl; Han G. Brunner; August F. Deutman; Carel B. Hoyng; Frans P.M. Cremers
• Keywords: Stargardt disease; ABCA4

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.