title: Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers.
abstract: OBJECTIVE
  We determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene.
  
  
  METHODS
  A total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis.
  
  
  RESULTS
  Several distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]).
  
  
  CONCLUSIONS
  The PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets.
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas, United States 2Department of Ophthalmology and Visual Sciences, Carver College of Medicine, Stephen A. Wynn Institute for Vision Research, Universit.
authors: Suma P
authors: SP
authors: Shankar
authors: Retina Foundation of the Southwest and Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
authors: Dianna K
authors: DK
authors: Hughbanks-Wheaton
authors: Retina Foundation of the Southwest and Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
authors: David G
authors: DG
authors: Birch
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas, United States.
authors: Lori S
authors: LS
authors: Sullivan
authors: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States.
authors: Karen N
authors: KN
authors: Conneely
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas, United States.
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, University of Iowa, Iowa City, Iowa, United States.
authors: Edwin M
authors: EM
authors: Stone
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas, United States 5Ruiz Department of Ophthalmology and Visual Science, University of Texas Health Science Center, Houston, Texas, United States.
authors: Stephen P
authors: SP
authors: Daiger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D003623:Dark Adaptation; D018450:Disease Progression; D004596:Electroretinography; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D064531:Peripherins / Q000235:genetics*; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D022821:RNA Splice Sites / Q000235:genetics*; D012160:Retina / Q000503:physiopathology; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology; D055815:Young Adult
chemical_list: C578997:PRPH2 protein, human; D064531:Peripherins; D022821:RNA Splice Sites