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Human Molecular Genetics Advance Access originally published online on August 15, 2005
Human Molecular Genetics 2005 14(19):2769-2778; doi:10.1093/hmg/ddi310
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© The Author 2005. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oupjournals.org

ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies

Wojciech Wiszniewski1, Charles M. Zaremba1, Alexander N. Yatsenko1, Milan Jamrich1, Theodore G. Wensel2, Richard Alan Lewis1,3,4,5 and James R. Lupski1,3,6,*

1Department of Molecular and Human Genetics, 2Department of Biochemistry, 3Department of Pediatrics and 4Department of Medicine and 5Department of Ophthalmology, Baylor College of Medicine and 6Texas Children Hospital, Houston, TX, USA

* To whom correspondence should be addressed at: Department of Molecular and Human Genetics, Baylor College of Medicine, Room No. 604B, One Baylor Plaza, Houston, TX 77030, USA. Tel: +1 7137986530; Fax: +1 7137985073; Email: jlupski{at}bcm.tmc.edu

Received June 17, 2005; Accepted August 9, 2005

ABCA4, also called ABCR, is a retinal-specific member of the ATP-binding cassette (ABC) family that functions in photoreceptor outer segments as a flipase of all-trans retinal. Homozygous and compound heterozygous ABCA4 mutations are associated with various autosomal recessive retinal dystrophies, whereas heterozygous ABCA4 mutations have been associated with dominant susceptibility to age-related macular degeneration in both humans and mice. We analyzed a cohort of 29 arRP families for the mutations in ABCA4 with a commercial microarray, ABCR-400 in addition to direct sequencing and segregation analysis, and identified both mutant alleles in two families (7%): compound heterozygosity for missense (R602W) and nonsense (R408X) alleles and homozygosity for a complex [L541P; A1038V] allele. The missense mutations were analyzed functionally in the photoreceptors of Xenopus laevis tadpoles, which revealed mislocalization of ABCA4 protein. These mutations cause retention of ABCA4 in the photoreceptor inner segment, likely by impairing correct folding, resulting in the total absence of physiologic protein function. Patients with different retinal dystrophies harboring two misfolding alleles exhibit early age-of-onset (AO) (5–12 years) of retinal disease. Our data suggest that a class of ABCA4 mutants may be an important determinant of the AO of disease.


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