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

Wojciech Wiszniewski, Charles M. Zaremba, Alexander N. Yatsenko, Milan Jamrich, Theodore G. Wensel, Richard Alan Lewis, James R. Lupski

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)2769-2778
Number of pages10
JournalHuman Molecular Genetics
Volume14
Issue number19
DOIs
StatePublished - Oct 2005
Externally publishedYes

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Retinal Dystrophies
Alleles
Mutation
Age of Onset
Retinal Diseases
Xenopus laevis
Macular Degeneration
Missense Mutation
Larva
Proteins
Adenosine Triphosphate

ASJC Scopus subject areas

  • Genetics

Cite this

Wiszniewski, W., Zaremba, C. M., Yatsenko, A. N., Jamrich, M., Wensel, T. G., Lewis, R. A., & Lupski, J. R. (2005). ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. Human Molecular Genetics, 14(19), 2769-2778. https://doi.org/10.1093/hmg/ddi310

ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. / Wiszniewski, Wojciech; Zaremba, Charles M.; Yatsenko, Alexander N.; Jamrich, Milan; Wensel, Theodore G.; Lewis, Richard Alan; Lupski, James R.

In: Human Molecular Genetics, Vol. 14, No. 19, 10.2005, p. 2769-2778.

Research output: Contribution to journalArticle

Wiszniewski, W, Zaremba, CM, Yatsenko, AN, Jamrich, M, Wensel, TG, Lewis, RA & Lupski, JR 2005, 'ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies', Human Molecular Genetics, vol. 14, no. 19, pp. 2769-2778. https://doi.org/10.1093/hmg/ddi310
Wiszniewski, Wojciech ; Zaremba, Charles M. ; Yatsenko, Alexander N. ; Jamrich, Milan ; Wensel, Theodore G. ; Lewis, Richard Alan ; Lupski, James R. / ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. In: Human Molecular Genetics. 2005 ; Vol. 14, No. 19. pp. 2769-2778.
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