Autosomal recessive retinitis pigmentosa due to ABCA4 mutations: clinical, pathologic, and molecular characterization

Robert F Mullins; Markus H Kuehn; Roxana A Radu; G Stephanie Enriquez; Jade S East; Emily I Schindler; Gabriel H Travis; Edwin M Stone

doi:10.1167/iovs.12-9477

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Autosomal recessive retinitis pigmentosa due to ABCA4 mutations: clinical, pathologic, and molecular characterization

Journal article

Open access

Peer reviewed

Autosomal recessive retinitis pigmentosa due to ABCA4 mutations: clinical, pathologic, and molecular characterization

Robert F Mullins, Markus H Kuehn, Roxana A Radu, G Stephanie Enriquez, Jade S East, Emily I Schindler, Gabriel H Travis and Edwin M Stone

Investigative ophthalmology & visual science, Vol.53(4), pp.1883-1894

04/18/2012

DOI: 10.1167/iovs.12-9477

PMCID: PMC3995570

PMID: 22395892

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Abstract

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. 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. 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. 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.

Electroretinography

Genetic Predisposition to Disease

Oligonucleotide Array Sequence Analysis

Rod Cell Outer Segment - metabolism

Humans

Retinitis Pigmentosa - genetics

Retinitis Pigmentosa - metabolism

Male

Retinitis Pigmentosa - diagnosis

DNA - genetics

ATP-Binding Cassette Transporters - genetics

Pedigree

ATP-Binding Cassette Transporters - metabolism

Rod Cell Outer Segment - pathology

Adult

Female

Mutation

Cadaver

Details

Title: Subtitle: Autosomal recessive retinitis pigmentosa due to ABCA4 mutations: clinical, pathologic, and molecular characterization
Creators: Robert F Mullins - Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, USA
Markus H Kuehn
Roxana A Radu
G Stephanie Enriquez
Jade S East
Emily I Schindler
Gabriel H Travis
Edwin M Stone
Resource Type: Journal article
Publication Details: Investigative ophthalmology & visual science, Vol.53(4), pp.1883-1894
DOI: 10.1167/iovs.12-9477
PMID: 22395892
PMCID: PMC3995570
NLM abbreviation: Invest Ophthalmol Vis Sci
ISSN: 0146-0404
eISSN: 1552-5783
Publisher: United States
Grant note: R01 EY019485 / NEI NIH HHS GM58939 / NIGMS NIH HHS R01 EY016822 / NEI NIH HHS EY-019485 / NEI NIH HHS EY-016822 / NEI NIH HHS EY-017451 / NEI NIH HHS R01 EY016822-06 / NEI NIH HHS R01 EY017451 / NEI NIH HHS R01 EY016822-07 / NEI NIH HHS R01 EY016822-08 / NEI NIH HHS R01 EY022044 / NEI NIH HHS
Language: English
Date published: 04/18/2012
Academic Unit: Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983980077702771

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