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Human Molecular Genetics, 2001, Vol. 10, No. 23 2671-2678
© 2001 Oxford University Press

Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration

Noah F. Shroyer1,2, Richard Alan Lewis2,3,4,5,7, Alexander N. Yatsenko2, Theodore G. Wensel1,6 and James R. Lupski1,2,3,+

1Program in Cell and Molecular Biology, 2Department of Molecular and Human Genetics, 3Department of Pediatrics, 4Department of Medicine, 5Department of Ophthalmology, 6Department of Biochemistry and 7The Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA

Mutations in ABCR (ABCA4) have been reported to cause a spectrum of autosomal recessively inherited retinopathies, including Stargardt disease (STGD), cone–rod dystrophy and retinitis pigmentosa. Individuals heterozygous for ABCR mutations may be predisposed to develop the multifactorial disorder age-related macular degeneration (AMD). We hypothesized that some carriers of STGD alleles have an increased risk to develop AMD. We tested this hypothesis in a cohort of families that manifest both STGD and AMD. With a direct-sequencing mutation detection strategy, we found that AMD-affected relatives of STGD patients are more likely to be carriers of pathogenic STGD alleles than predicted based on chance alone. We further investigated the role of AMD-associated ABCR mutations by testing for expression and ATP-binding defects in an in vitro biochemical assay. We found that mutations associated with AMD have a range of assayable defects ranging from no detectable defect to apparent null alleles. Of the 21 missense ABCR mutations reported in patients with AMD, 16 (76%) show abnormalities in protein expression, ATP-binding or ATPase activity. We infer that carrier relatives of STGD patients are predisposed to develop AMD.

+ To whom correspondence should be addressed at: Baylor College of Medicine, One Baylor Plaza, 604B, Houston, TX 77030, USA. Tel: +1 713 798 6530; Fax: +1 713 798 5073; Email: jlupski@bcm.tmc.eduPresent address:Noah F. Shroyer, Howard Hughes Medical Institute, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA


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