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Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy.

ABSTRACT: We report mutations in the gene for topoisomerase I-binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP) linked to chromosome 9p21.1 (locus RP31). A positional-cloning approach, together with the use of bioinformatics, identified TOPORS (comprising three exons and encoding a protein of 1,045 aa) as the gene responsible for adRP. Mutations that include an insertion and a deletion have been identified in two adRP-affected families--one French Canadian and one German family, respectively. Interestingly, a distinct phenotype is noted at the earlier stages of the disease, with an unusual perivascular cuff of retinal pigment epithelium atrophy, which was found surrounding the superior and inferior arcades in the retina. TOPORS is a RING domain-containing E3 ubiquitin ligase and localizes in the nucleus in speckled loci that are associated with promyelocytic leukemia bodies. The ubiquitous nature of TOPORS expression and a lack of mutant protein in patients are highly suggestive of haploinsufficiency, rather than a dominant negative effect, as the molecular mechanism of the disease and make rescue of the clinical phenotype amenable to somatic gene therapy.

SUBMITTER: Chakarova CF

PROVIDER: S-EPMC2265653 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy.

Chakarova Christina F CF Papaioannou Myrto G MG Khanna Hemant H Lopez Irma I Waseem Naushin N Shah Amna A Theis Torsten T Friedman James J Maubaret Cecilia C Bujakowska Kinga K Veraitch Brotati B Abd El-Aziz Mai M MM Prescott De Quincy de Q Parapuram Sunil K SK Bickmore Wendy A WA Munro Peter M G PM Gal Andreas A Hamel Christian P CP Marigo Valeria V Ponting Chris P CP Wissinger Bernd B Zrenner Eberhart E Matter Karl K Swaroop Anand A Koenekoop Robert K RK Bhattacharya Shomi S SS

American journal of human genetics 20070926 5

We report mutations in the gene for topoisomerase I-binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP) linked to chromosome 9p21.1 (locus RP31). A positional-cloning approach, together with the use of bioinformatics, identified TOPORS (comprising three exons and encoding a protein of 1,045 aa) as the gene responsible for adRP. Mutations that include an insertion and a deletion have been identified in two adRP-affected families--one French Canadian and one ...[more]

PMID: 17924349

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Project description:BackgroundRetinitis pigmentosa (RP) is an inherited retinal disease that results in photoreceptor degeneration, leading to severe vision loss or blindness. Due to its genetic heterogeneity, developing a new gene therapy to correct every genetic mutation contributing to its progression is infeasible. Photoreceptor transplantation can be harnessed to restore vision; however, this approach is limited by poor cell survival and synaptic integration into the neural retina. Thus, we developed a combined cell and gene therapy that is expected to protect photoreceptors in most, if not all, cases of RP.MethodsHuman embryonic stem cells (hESCs) modified with our FailSafe™ system were genetically engineered to overexpress sCX3CL1, an inhibitor of microglia activation that has been shown to preserve photoreceptor survival and function in mouse models of RP, independent of the genetic cause. These cells were differentiated into human retinal pigment epithelium (hRPE) cells and used as therapeutic cells due to their longevity and safety, both of which have been demonstrated in preclinical and clinical studies. Transgenic hRPE were delivered into the subretinal space of immunodeficient mice and the rd10 mouse model of RP to evaluate donor cell survival and retention of transgene expression. The outer nuclear layer was quantified to assess photoreceptor protection.ResultsTransgenic FailSafe™ hRPE (FS-hRPE) cells can survive for at least four months in the retina of immunodeficient mice and retain transgene expression. However, these cells do not persist beyond two weeks post-injection in the retina of immunocompetent rd10 recipients, despite Cyclosporine A treatment. Nevertheless, sCX3CL1-expressing FailSafe™ hRPE cells prevented photoreceptor degeneration in a local acting manner during the duration of their presence in the subretinal space.ConclusionsTransgenic hESCs differentiate into hRPE cells and retain sCX3CL1 transgene expression both in vitro and in vivo. Moreover, hRPE cells delivered to the subretinal space of rd10 mice prevented photoreceptor degeneration in a local-acting manner, suggesting that this approach could have applications for preserving photoreceptors in specific subregions of the retina, such as the macula. Overall, our study not only reveals the potential of a combined cell and gene therapy for the treatment of RP, but also the possibility of using hRPE cells to deliver therapeutic biologics in situ to treat diseases over long-term.

Dataset Information

Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy.

Publications

Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy.

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