TY - JOUR
T1 - ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies
AU - Wiszniewski, Wojciech
AU - Zaremba, Charles M.
AU - Yatsenko, Alexander N.
AU - Jamrich, Milan
AU - Wensel, Theodore G.
AU - Lewis, Richard Alan
AU - Lupski, James R.
N1 - Funding Information:
We thank all participating families and their attending physicians for their willing and continued participation in these studies. We also thank Dr Suzanne Leal for assistance with data analysis. This study was supported in part by the National Eye Institute, NIH grant EY13255 to J.R.L. Funding to pay the Open Access publication charges for this article was provided by Cullen Professorship funds to J.R.L.
PY - 2005/10
Y1 - 2005/10
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddi310
DO - 10.1093/hmg/ddi310
M3 - Article
C2 - 16103129
AN - SCOPUS:26444510862
SN - 0964-6906
VL - 14
SP - 2769
EP - 2778
JO - Human molecular genetics
JF - Human molecular genetics
IS - 19
ER -