title: Homozygosity for a novel ABCA4 founder splicing mutation is associated with progressive and severe Stargardt-like disease.
abstract: OBJECTIVE
  To clinically characterize and genetically analyze members of six families who reside in the same village and manifest a rare form of retinal degeneration.
  
  
  METHODS
  Ophthalmic evaluation included a full clinical examination, perimetry, color vision testing, and electroretinography. Genomic DNA was screened for ABCA4 mutations with the use of microarray analysis and direct sequencing. RNA analysis was performed with RT-PCR and sequencing.
  
  
  RESULTS
  The authors recruited 15 patients with a unique retinal disease who are members of six highly consanguineous Arab-Muslim families from a single village. During early stages of disease, funduscopic and angiographic findings as well as retinal function resemble those of Stargardt disease. However, later in life, severe, widespread cone-rod degeneration ensues. Marked progressive involvement of the retinal periphery distinguishes this phenotype from classic Stargardt disease. Genetic analysis of ABCA4 revealed two novel deletions, p.Cys1150del and c.4254-15del23. One patient, who was a compound heterozygote, manifested typical Stargardt disease. The remaining 14 patients were homozygote for the c.4254- 15del23 intronic deletion and had the progressive form of disease. We identified an identical ABCA4 haplotype in all alleles carrying this mutation, indicating a founder mutation. Detailed RT-PCR analysis in normal retina and lymphoblastoid cells revealed expression of the full-length ABCA4 transcript and three novel transcripts produced by alternative splicing. The full-length ABCA4 transcript, however, could not be detected in lymphoblastoid cells of affected homozygote patients.
  
  
  CONCLUSIONS
  These results expand the genotype-phenotype correlation of ABCA4, showing that homozygosity for the novel c.4254-15del23 splicing mutation is associated with a severe progressive form of disease.
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Beit-Ya'acov
authors.forename: Liliana
authors.initials: L
authors.lastname: Mizrahi-Meissonnier
authors.forename: Alexey
authors.initials: A
authors.lastname: Obolensky
authors.forename: Carmit
authors.initials: C
authors.lastname: Landau
authors.forename: Anat
authors.initials: A
authors.lastname: Blumenfeld
authors.forename: Ada
authors.initials: A
authors.lastname: Rosenmann
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005451:Fluorescein Angiography; D018703:Founder Effect; D018095:Germ-Line Mutation; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D012160:Retina / Q000503:physiopathology; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014792:Visual Acuity; D014794:Visual Fields
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters