title: A homozygous deletion in RPE65 in a small Sardinian family with autosomal recessive retinal dystrophy.
abstract: OBJECTIVE
  We have been engaged in an ongoing study to screen candidate genes for mutations in small families with various forms of autosomal recessive retinal dystrophy. Here we report the screening of a cohort of 14 families from Sardinia for mutations in the genes encoding the alpha- and beta-subunits of cGMP-phosphodiesterase and RPE65 (PDE6A, PDE6B, and RPE65).
  
  
  METHODS
  Haplotype analysis was performed on each family using simple sequence repeat markers closely flanking or within each of the three gene candidates. For families in which a gene could not be ruled out from segregating with disease, exons of the gene from proband DNAs were screened for mutations by SSCPE (single strand conformation polymorphism electrophoresis). All variants found by SSCPE were sequenced directly.
  
  
  RESULTS
  By haplotype analysis, 6/14, 11/14, and 4/13 families were ruled out for PDE6A, PDE6B, and RPE65, respectively. A few variants were found in the proband DNAs of the remaining families, but only one was significant: a 20 bp deletion in exon 4 of RPE65. The deletion co-segregated with disease in one family and caused a frame shift that produces a stop codon downstream. It was absent from the other Sardinian families that we tested, and from Sardinian and North American controls. Results of studies of phenotype in homozygotes and heterozygotes in this Sardinian family are compared with those from a non-Sardinian family recently reported to have the same RPE65 mutation.
  
  
  CONCLUSIONS
  This RPE65 mutation, which appears to be quite restricted in its occurrence in Sardinia, leads to childhood onset severe retinal dystrophy or Leber congenital amaurosis. Affecteds of the other 13 plus two additional families were diagnosed with arRP. This family lived in an area of Sardinia where none of the others lived suggesting different ancestral origins.
authors.affiliation: Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA 90095-7008, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Poehner
authors.forename: M
authors.initials: M
authors.lastname: Fossarello
authors.forename: A L
authors.initials: AL
authors.lastname: Rapoport
authors.forename: T S
authors.initials: TS
authors.lastname: Aleman
authors.forename: A V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: S G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: A F
authors.initials: AF
authors.lastname: Wright
authors.forename: M
authors.initials: M
authors.lastname: Danciger
authors.forename: D B
authors.initials: DB
authors.lastname: Farber
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000235:genetics; D001483:Base Sequence; D002352:Carrier Proteins; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004591:Electrophoresis, Polyacrylamide Gel; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D010857:Pigment Epithelium of Eye / Q000473:pathology; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics*; D012162:Retinal Degeneration / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D014792:Visual Acuity; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D002352:Carrier Proteins; D005136:Eye Proteins; D011506:Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase