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Andrew R. Webster, Elise Héon, Andrew J. Lotery, Kimberlie Vandenburgh, Thomas L. Casavant, Kean T. Oh, Gretel Beck, Gerald A. Fishman, Byron L. Lam, Alex Levin, John R. Heckenlively, Samuel G. Jacobson, Richard G. Weleber, Val C. Sheffield, Edwin M. Stone; An Analysis of Allelic Variation in the ABCA4 Gene. Invest. Ophthalmol. Vis. Sci. 2001;42(6):1179-1189.
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purpose. To assess the allelic variation of the ATP-binding transporter protein
methods. A combination of single-strand conformation polymorphism (SSCP) and
automated DNA sequencing was used to systematically screen this gene
for sequence variations in 374 unrelated probands with a clinical
diagnosis of Stargardt disease, 182 patients with age-related macular
degeneration (AMD), and 96 normal subjects.
results. There was no significant difference in the proportion of any single
variant or class of variant between the control and AMD groups. In
contrast, truncating variants, amino acid substitutions, synonymous
codon changes, and intronic variants were significantly enriched in
patients with Stargardt disease when compared with their presence in
subjects without Stargardt disease (Kruskal–Wallis P < 0.0001 for each variant group). Overall, there
were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid
substitutions, and 45 instances of 33 truncating variants.
conclusions. Of the 97 amino acid substitutions, 11 occurred at a frequency that
made them unlikely to be high-penetrance recessive disease-causing
variants (HPRDCV). After accounting for variants in cis,
one or more changes that were compatible with HPRDCV were found on 35%
of all Stargardt-associated alleles overall. The nucleotide diversity
of the ABCA4 coding region, a collective measure of the
number and prevalence of polymorphic sites in a region of DNA, was
found to be 1.28, a value that is 9 to 400 times greater than that of
two other macular disease genes that were examined in a similar fashion
(VMD2 and EFEMP1).
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