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(Investigative Ophthalmology and Visual Science. 2000;41:892-897.)
© 2000 by The Association for Research in Vision and Ophthalmology, Inc.

New ABCR Mutations and Clinical Phenotype in Italian Patients with Stargardt Disease

Francesca Simonelli1, Francesco Testa1,2, Giuseppe de Crecchio3, Ernesto Rinaldi1, Amy Hutchinson4, Andrew Atkinson6, Michael Dean6, Michele D’Urso2 and Rando Allikmets4,5

1 From the Eye Clinic, Second University of Naples; 2 International Institute of Genetics and Biophysics, Consiglio Nazioale delle Ricerche, Naples; and 3 Eye Clinic, Federico II University, Naples, Italy; 4 Departments of Ophthalmology and 5 Pathology, Columbia University, New York, New York; and 6 Laboratory of Genomic Diversity, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, Maryland.

PURPOSE. To assess the mutation spectrum in the ABCR gene and clinical phenotypes in Italian families with autosomal recessive Stargardt disease (STGD1) and fundus flavimaculatus (FFM).

METHODS. Eleven families from southern Italy, including 18 patients with diagnoses of STGD1, were clinically examined. Ophthalmologic examination included kinetic perimetry, electrophysiological studies, and fluorescein angiography. DNA samples of the affected individuals and their family members were analyzed for variants in all 50 exons of the ABCR gene by a combination of single-strand conformation polymorphism analysis and direct sequencing techniques.

RESULTS. Ten ABCR variants were identified in 16 (73%) of 22 mutant alleles of patients with STGD1. Five mutations of 10 that were found had not been previously described. The majority of variants represent missense amino acid substitutions, and all mutant alleles cosegregate with the disease in the respective families. These ABCR variants were not detected in 170 unaffected control individuals (340 chromosomes) of Italian origin. 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.

CONCLUSIONS. Patients from southern Italy with Stargardt disease show extensive allelic heterogeneity of the ABCR gene, concordant with previous observations in patients with STGD1 from different ethnic groups. Half the mutations identified in this study had not been previously described in patients with STGD1. Screening of increasingly large numbers of patients would help to determine whether this can be explained by ethnic differences, or is an indicator of extensive allelic heterogeneity of ABCR in STGD1 and other eye diseases. In 6 (55%) of 11 families, the first-degree relatives of patients with STGD1 were diagnosed with early AMD, supporting the previous observation that some STGD1 alleles are also associated with AMD.




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