title: Autosomal recessive retinitis pigmentosa due to ABCA4 mutations: clinical, pathologic, and molecular characterization.
abstract: OBJECTIVE
  Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous condition characterized by progressive loss of retinal photoreceptor cells. In order to gain new insights into the pathogenesis of ARRP, we evaluated the morphological, biochemical, and gene expression changes in eyes from a human donor with ARRP due to mutations in the ABCA4 gene.
  
  
  METHODS
  Eyes were obtained postmortem from a donor with end-stage retinitis pigmentosa. The coding sequences of the RDS, RHO, and ABCA4 genes were screened for disease-causing mutations. Morphological changes in different regions of the retina were examined histologically, and levels of lipofuscin-associated bisretinoids were measured. Gene expression was examined in retinal/choroidal tissue using microarray analysis, and all parameters were compared to those in unaffected control donors.
  
  
  RESULTS
  Genetic analysis of the donor's DNA identified two mutations in the ABCA4 gene, IVS14+1G > C and Phe1440del1 cT, each on a separate allele. Morphological evaluation revealed complete loss of the outer nuclear layer, remodeling of the inner retina, loss of retinal vasculature, and regional neovascularization. The retinal pigment epithelium and choriocapillaris exhibited regional preservation. Microarray analysis revealed loss of photoreceptor cell-associated transcripts, with preservation of multiple genes expressed specifically in inner retinal neurons.
  
  
  CONCLUSIONS
  The persistence of transcripts expressed by inner retinal neurons suggests that despite significant plasticity that occurs during retinal degeneration, bipolar cells and ganglion cells remain at least partially differentiated. Findings from this study suggest that some forms of therapy currently under investigation may have benefit even in advanced retinal degeneration.
authors.affiliation: Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Mullins
authors.forename: Markus H
authors.initials: MH
authors.lastname: Kuehn
authors.forename: Roxana A
authors.initials: RA
authors.lastname: Radu
authors.forename: G Stephanie
authors.initials: GS
authors.lastname: Enriquez
authors.forename: Jade S
authors.initials: JS
authors.lastname: East
authors.forename: Emily I
authors.initials: EI
authors.lastname: Schindler
authors.forename: Gabriel H
authors.initials: GH
authors.lastname: Travis
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D002102:Cadaver; D004247:DNA / Q000235:genetics*; D004596:Electroretinography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D012374:Rod Cell Outer Segment / Q000378:metabolism / Q000473:pathology*
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D004247:DNA