title: An analysis of allelic variation in the ABCA4 gene.
abstract: OBJECTIVE
  To assess the allelic variation of the ATP-binding transporter protein (ABCA4).
  
  
  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).
authors.affiliation: Department of Ophthalmology, The University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Webster
authors.forename: E
authors.initials: E
authors.lastname: Héon
authors.forename: A J
authors.initials: AJ
authors.lastname: Lotery
authors.forename: K
authors.initials: K
authors.lastname: Vandenburgh
authors.forename: T L
authors.initials: TL
authors.lastname: Casavant
authors.forename: K T
authors.initials: KT
authors.lastname: Oh
authors.forename: G
authors.initials: G
authors.lastname: Beck
authors.forename: G A
authors.initials: GA
authors.lastname: Fishman
authors.forename: B L
authors.initials: BL
authors.lastname: Lam
authors.forename: A
authors.initials: A
authors.lastname: Levin
authors.forename: J R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: S G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: R G
authors.initials: RG
authors.lastname: Weleber
authors.forename: V C
authors.initials: VC
authors.lastname: Sheffield
authors.forename: E M
authors.initials: EM
authors.lastname: Stone
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000483:Alleles; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D008268:Macular Degeneration / Q000235:genetics*; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA
chemical_list: D018528:ATP-Binding Cassette Transporters