Comparison of structural progression between ciliopathy and non-ciliopathy associated with autosomal recessive retinitis pigmentosa

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Abstract

Background

To evaluate and compare the progression of ciliopathy and non-ciliopathy autosomal recessive Retinitis Pigmentosa patients (arRP) by measuring the constriction of hyperautofluorescent rings in fundus autofluorescence (FAF) images and the progressive shortening of the ellipsoid zone line width obtained by spectral-domain optical coherence tomography (SD-OCT).

Results

For the ciliopathy group, the estimated mean shortening of the ellipsoid zone line was 259 μm per year and the ring area decreased at a rate of 2.46 mm ² per year. For the non-ciliopathy group, the estimated mean shortening of the ellipsoid zone line was 84 μm per year and the ring area decreased at a rate of 0.7 mm ² per year.

Conclusions

Our study was able to quantify and compare the loss of EZ line width and short-wavelength autofluorescence (SW-AF) ring constriction progression over time for ciliopathy and non-ciliopathy arRP genes. These results may serve as a basis for modeling RP disease progression, and furthermore, they could potentially be used as endpoints in clinical trials seeking to promote cone and rod survival in RP patients.

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Most cited references 24

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Centrioles, centrosomes, and cilia in health and disease.

Erich Nigg, Jordan W. Raff (2009)

Centrioles are barrel-shaped structures that are essential for the formation of centrosomes, cilia, and flagella. Here we review recent advances in our understanding of the function and biogenesis of these organelles, and we emphasize their connection to human disease. Deregulation of centrosome numbers has long been proposed to contribute to genome instability and tumor formation, whereas mutations in centrosomal proteins have recently been genetically linked to microcephaly and dwarfism. Finally, structural or functional centriole aberrations contribute to ciliopathies, a variety of complex diseases that stem from the absence or dysfunction of cilia.

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Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa.

R Vervoort, A. Lennon, A Bird … (2000)

The gene RPGR was previously identified in the RP3 region of Xp21.1 and shown to be mutated in 10-20% of patients with the progressive retinal degeneration X-linked retinitis pigmentosa (XLRP). The mutations predominantly affected a domain homologous to RCC1, a guanine nucleotide exchange factor for the small GTPase Ran, although they were present in fewer than the 70-75% of XLRP patients predicted from linkage studies. Mutations in the RP2 locus at Xp11.3 were found in a further 10-20% of XLRP patients, as predicted from linkage studies. Because the mutations in the remainder of the XLRP patients may reside in undiscovered exons of RPGR, we sequenced a 172-kb region containing the entire gene. Analysis of the sequence disclosed a new 3' terminal exon that was mutated in 60% of XLRP patients examined. This exon encodes 567 amino acids, with a repetitive domain rich in glutamic acid residues. The sequence is conserved in the mouse, bovine and Fugu rubripes genes. It is preferentially expressed in mouse and bovine retina, further supporting its importance for retinal function. Our results suggest that mutations in RPGR are the only cause of RP3 type XLRP and account for the disease in over 70% of XLRP patients and an estimated 11% of all retinitis pigmentosa patients.

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A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3).

Augusto Carvalho, Gregory Bird, Elaine Wright … (1996)

X-linked retinitis pigmentosa (xlRP) is a severe progressive retinal degeneration which affects about 1 in 25,000 of the population. The most common form of xlRP, RP3, has been localised to the interval between CYBB and OTC in Xp21.1 by linkage analysis and deletion mapping. Identification of microdeletions within this region has now led to the positional cloning of a gene, RPGR, that spans 60 kg of genomic DNA and is ubiquitously expressed. The predicted 90 kD protein contains in its N-terminal half a tandem repeat structure highly similar to RCC1 (regulator of chromosome condensation), suggesting an interaction with a small GTPase. The C-terminal half contains a domain, rich in acidic residues, and ends in a potential isoprenylation anchorage site. The two intragenic deletions, two nonsense and three missense mutations within conserved domains provide evidence that RPGR (retinitis pigmentosa GTPase regulator) is the RP3 gene.

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Author and article information

Contributors

Vitor K. L. Takahashi: vkazuolt@hotmail.com

Christine L. Xu: christinexu787@gmail.com

Júlia T. Takiuti: juliatakiuti@hotmail.com

Mary Ben L. Apatoff: mblapatoff@gmail.com

Jimmy K. Duong: jkd2108@cumc.columbia.edu

Vinit B. Mahajan: mahajanlab@gmail.com

Stephen H. Tsang: 212-342-1189 , gene.editing@gmail.com

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 1 August 2019

Publication date PMC-release: 1 August 2019

Publication date Collection: 2019

Volume: 14

Electronic Location Identifier: 187

Affiliations

[1 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Ophthalmology, , Columbia University, ; New York, NY USA

[2 ]ISNI 0000000419368729, GRID grid.21729.3f, Jonas Children’s Vision Care, and the Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology & Cell Biology, Columbia Stem Cell Initiative, Institute of Human Nutrition, , Columbia University, ; New York, NY USA

[3 ]ISNI 0000 0001 0514 7202, GRID grid.411249.b, Department of Ophthalmology, , Federal University of São Paulo, ; São Paulo, Brazil

[4 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Division of Ophthalmology, , University of São Paulo Medical School, ; São Paulo, Brazil

[5 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Biostatistics, , Columbia University, ; New York, NY USA

[6 ]ISNI 0000000419368956, GRID grid.168010.e, Byers Eye Institute, Omics Laboratory, Department of Ophthalmology, , Stanford University School of Medicine, ; Palo Alto, CA USA

[7 ]ISNI 0000 0004 0419 2556, GRID grid.280747.e, Veterans Affairs Palo Alto Health Care System, ; Palo Alto, CA USA

[8 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Pathology & Cell Biology, Stem Cell Initiative (CSCI), Institute of Human Nutrition, College of Physicians and Surgeons, , Columbia University, ; New York, NY USA

[9 ]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Harkness Eye Institute, , Columbia University Medical Center, ; 635 West 165th Street, Box 212, New York, NY 10032 USA

Article

Publisher ID: 1163

DOI: 10.1186/s13023-019-1163-9

PMC ID: 6676605

PubMed ID: 31370859

SO-VID: 57afeb7a-babb-49d9-b3aa-0d42e0ce7fdd

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 3 January 2019

Date accepted : 22 July 2019

Funding

Funded by: National Institutes of Health

Award ID: P30EY019007

Award ID: R01EY024698

Award ID: R01EY026682