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S. Kamakari, P. Stamatiou, T. Panagiotoglou, C. Tsika, M. Tsilimbaris; Microarray-Based Mutation Analysis of the ABCA4 Gene in Greek Patients With Stargardt Disease: Evidence of Three Prevalent Mutated Alleles. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4118.
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© ARVO (1962-2015); The Authors (2016-present)
Stargardt (STGD) disease, characterized by central vision impairment, has a juvenile to young adult onset and is the most common form of autosomal recessive macular degeneration. The disease is caused by alterations in the gene encoding the photoreceptor-specific ATP-binding cassette transporter (ABCA4). STGD patients in the Greek population have not been previously genetically characterized for sequence variations in the ABCA4 gene.
To evaluate the mutation spectrum in STGD patients from Greece, 19 unrelated patients were analyzed using the ABCR400 microarray and results were confirmed by direct sequencing.
Two potential mutant alleles were found in 6/19 cases (31.6%), whereas in 6/19 cases (31.6%) only one allele could be identified leading to an overall mutation detection rate of 63.2%. We identified a major disease-associated allele, G1961E, which accounted for 27.8% (5/18) of the mutated alleles. Other frequent ABCA4 alleles in the Greek STGD population included the IVS40+5 G>A splice site variant (16.7% of the detected mutated alleles), the complex allele L541P/A1038V (16.7%), whereas L541P alone or as a complex allele with A1038V was identified with a total detection rate of 22.2%. Based on the mutation spectrum among Greek STGD patients, resulting from the ABCR400 microarray screening, two unrelated patients were subjected to selective screening of the most frequently mutated exons 12,/21, 40 and 42 ofthe ABCA4 gene. Mutations were identified in both patients and involved the complex allele L541P/A1038V in one patient in heterozygous state and the L541P allele and the IVS40+5 G>A splice site variant both in heterozygous state in the second patient. The latter data indicates that an initial cost-effective selective exon pre-screening of all Greek STGD patients can be incorporated in our mutational analysis.
This is the first systematic study to assess the mutation spectrum of the ABCA4 gene underlying STGD disease in Greece. We identified three prevalent disease-associated alleles, G1961E, L541P alone or as a complex L541P/A1038V allele and the IVS40+5 G>A which accounted for 27.8 %, 22.2% and 16.7% of the mutated alleles, respectively. The overall detection rate by microarray analysis and selective sequencing of the ABCA4 gene was 66.7%. Further studies will help in the definition of the genotype-phenotype relationship in ABCA4-associated retinal dystrophies among Greek patients.
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