title: Founder Effect of a c.828+3A&gt;T Splice Site Mutation in Peripherin 2 (PRPH2) Causing Autosomal Dominant Retinal Dystrophies.
abstract: OBJECTIVE
  Screening for splice site mutation c.828+3A>T in the peripherin 2 (PRPH2) gene should be a high priority in families with highly variable retinal dystrophies. The correction of missplicing is a potential therapeutic target.
  
  
  OBJECTIVE
  To determine the prevalence, genetic origin, and molecular mechanism of a donor c.828+3A>T mutation in the PRPH2 (peripherin 2, retinal degeneration slow) gene in individuals with retinal dystrophies.
  
  
  METHODS
  Case-control study that took place at the University of Texas Health Science Center, the University of Iowa, and the Retina Foundation of the Southwest, from January 1, 1987, to August 1, 2014, including affected individuals from 200 families with a diagnosis of autosomal dominant retinitis pigmentosa, 35 families with unspecified macular dystrophies, and 116 families with pattern dystrophy. Participants were screened for the c.828+3A>T mutation by restriction-enzyme digest, single-strand conformational polymorphism screening, or bidirectional sequencing. Haplotypes of polymorphic markers flanking the PRPH2 locus and sequence variants within the gene were determined by denaturing gel electrophoresis or automated capillary-based cycle sequencing. The effect of the splice site mutation on the PRPH2 transcript was analyzed using NetGene2, a splice prediction program and by the reverse transcription polymerase chain reaction of illegitimate transcripts from peripheral white blood cells.
  
  
  METHODS
  Results of testing for splice site mutation, haplotypes, and alternate transcripts.
  
  
  RESULTS
  The PRPH2 mutation was found in 97 individuals of 19 independently ascertained families with a clinical diagnosis of retinitis pigmentosa, macular dystrophy, and/or pattern dystrophy. All affected individuals also shared a rare haplotype of approximately 644 kilobase pairs containing the c.828+3A>T mutation, which extends from the short tandem repeat polymorphism D6S282 to c.1013G>A (rs434102, a single-nucleotide polymorphism) in exon 3 of PRPH2, suggesting this mutation is from a common ancestor and is a founder mutation. It has a prevalence of 2% in families diagnosed as having autosomal dominant retinitis pigmentosa and 10% in families with variable clinical diagnosis of pattern, macular, and retinal dystrophies. Individuals with the c.828+3A>T mutation expressed a PRPH2 transcript not found in control participants and that was consistent with abnormal splicing.
  
  
  CONCLUSIONS
  The PRPH2 c.828+3A>T splice site mutation is a frequent cause of inherited retinal dystrophies and is owing to the founder effect. The likely cause of disease is the missplicing of the PRPH2 message that results in a truncated protein product. Identifying the genetic etiology assists in more accurate management and possible future therapeutic options.
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston2Department of Ophthalmology and Visual Sciences, Carver College of Medicine, Stephen A. Wynn Institute for Vision Research, Howard Hughes Medical Institute.
authors: Suma P
authors: SP
authors: Shankar
authors: Retina Foundation of the Southwest, Dallas, Texas.
authors: David G
authors: DG
authors: Birch
authors: Department of Ophthalmology and Visual Science, University of Texas Health Science Center, Houston.
authors: Richard S
authors: RS
authors: Ruiz
authors: Retina Foundation of the Southwest, Dallas, Texas.
authors: Dianna K
authors: DK
authors: Hughbanks-Wheaton
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston.
authors: Lori S
authors: LS
authors: Sullivan
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston.
authors: Sara J
authors: SJ
authors: Bowne
authors: Department of Ophthalmology and Visual Sciences, Carver College of Medicine, Stephen A. Wynn Institute for Vision Research, Howard Hughes Medical Institute, University of Iowa, Iowa City.
authors: Edwin M
authors: EM
authors: Stone
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston6Department of Ophthalmology and Visual Science, University of Texas Health Science Center, Houston.
authors: Stephen P
authors: SP
authors: Daiger
mesh_terms: D001483:Base Sequence; D016022:Case-Control Studies; D018703:Founder Effect; D008040:Genetic Linkage; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D064531:Peripherins / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D022821:RNA Splice Sites / Q000235:genetics*; D058499:Retinal Dystrophies / Q000453:epidemiology / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: C578997:PRPH2 protein, human; D064531:Peripherins; D022821:RNA Splice Sites