title: ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy.
abstract: OBJECTIVE
  To determine the frequency and nature of mutations in the gene ABCA4 in a cohort of patients with bull's-eye maculopathy (BEM).
  
  
  METHODS
  A panel of 49 subjects (comprising 40 probands/families, 7 sibling pairs and a set of three sibs) with BEM, not attributable to toxic causes, was ascertained. Blood samples from each patient were used to extract genomic DNA, with subsequent mutation screening of the entire coding sequence of ABCA4, using single-strand conformational polymorphism (SSCP) analysis and direct sequencing.
  
  
  RESULTS
  Fourteen probands (35%) were found to have a potentially disease-causing ABCA4 sequence variant on at least one allele. Three patients had a Gly1961Glu missense mutation, the most common variant in Stargardt disease (STGD), with 2 of these subjects having a macular dystrophy (MD) phenotype and a second ABCA4 variant previously associated with STGD. The second most common STGD mutation, Ala1038Val, was seen in one patient with cone-rod dystrophy (CORD). Five novel ABCA4 variants were detected. Two sibships were identified with a similar intra-familial phenotype but discordant ABCA4 variants.
  
  
  CONCLUSIONS
  Variations in the ABCA4 gene are common in BEM. Two sibships showed discordant ABCA4 variants. One of these sibships illustrates that ABCA4 variants can be identified in families that have another molecular cause for their disease, due to the high prevalence of ABCA4 disease alleles in the population. The discordance evident in the second sibship may yet also be a chance finding in families with macular disease of another genetic cause, or it may represent a complex mode of inheritance determined/modified by the combination of ABCA4 alleles.
authors.affiliation: Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: M
authors.initials: M
authors.lastname: Michaelides
authors.forename: L L
authors.initials: LL
authors.lastname: Chen
authors.forename: M A
authors.initials: MA
authors.lastname: Brantley
authors.forename: J L
authors.initials: JL
authors.lastname: Andorf
authors.forename: E M
authors.initials: EM
authors.lastname: Isaak
authors.forename: S A
authors.initials: SA
authors.lastname: Jenkins
authors.forename: G E
authors.initials: GE
authors.lastname: Holder
authors.forename: A C
authors.initials: AC
authors.lastname: Bird
authors.forename: E M
authors.initials: EM
authors.lastname: Stone
authors.forename: A R
authors.initials: AR
authors.lastname: Webster
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000409:Alanine; D000483:Alleles; D015331:Cohort Studies; D005260:Female; D018698:Glutamic Acid; D005998:Glycine; D006801:Humans; D008266:Macula Lutea; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012164:Retinal Diseases / Q000235:genetics*; D035781:Siblings; D014633:Valine
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D018698:Glutamic Acid; D014633:Valine; D000409:Alanine; D005998:Glycine