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

Chakarova, CF; Papaioannou, MG; Khanna, H; Lopez, I; Waseem, N; Shah, A; Theis, T; Friedman, J; Maubaret, C; Bujakowska, K; Veraitch, B; Abd El-Aziz, MM; Prescott, DQ; Parapuram, SK; Bickmore, WA; Munro, PMG; Gal, A; Hamel, CP; Marigo, V; Ponting, CP; Wissinger, B; Zrenner, E; Matter, K; Swaroop, A; Koenekoop, RK; Bhattacharya, SS

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

Chakarova, CF Papaioannou, MG Khanna, H Lopez, I Waseem, N Shah, A Theis, T Friedman, J Maubaret, C Bujakowska, K Veraitch, B Abd El-Aziz, MM Prescott, DQ Parapuram, SK Bickmore, WA Munro, PMG Gal, A Hamel, CP Marigo, V Ponting, CP Wissinger, B Zrenner, E Matter, K Swaroop, A Koenekoop, RK Bhattacharya, SS

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Publication Type:: Journal Article
Citation:: Am J Hum Genet, 2007, 81 (5), pp. 1098 - 1103
Issue Date:: 2007-11

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Field	Value	Language
dc.contributor.author	Chakarova, CF	en_US
dc.contributor.author	Papaioannou, MG	en_US
dc.contributor.author	Khanna, H	en_US
dc.contributor.author	Lopez, I	en_US
dc.contributor.author	Waseem, N	en_US
dc.contributor.author	Shah, A	en_US
dc.contributor.author	Theis, T	en_US
dc.contributor.author	Friedman, J	en_US
dc.contributor.author	Maubaret, C	en_US
dc.contributor.author	Bujakowska, K	en_US
dc.contributor.author	Veraitch, B	en_US
dc.contributor.author	Abd El-Aziz, MM	en_US
dc.contributor.author	Prescott, DQ	en_US
dc.contributor.author	Parapuram, SK	en_US
dc.contributor.author	Bickmore, WA	en_US
dc.contributor.author	Munro, PMG	en_US
dc.contributor.author	Gal, A	en_US
dc.contributor.author	Hamel, CP	en_US
dc.contributor.author	Marigo, V	en_US
dc.contributor.author	Ponting, CP	en_US
dc.contributor.author	Wissinger, B	en_US
dc.contributor.author	Zrenner, E	en_US
dc.contributor.author	Matter, K	en_US
dc.contributor.author	Swaroop, A	en_US
dc.contributor.author	Koenekoop, RK	en_US
dc.contributor.author	Bhattacharya, SS	en_US
dc.date.available	2007-07-17	en_US
dc.date.issued	2007-11	en_US
dc.identifier.citation	Am J Hum Genet, 2007, 81 (5), pp. 1098 - 1103	en_US
dc.identifier.issn	0002-9297	en_US
dc.identifier.uri	http://hdl.handle.net/10453/4753
dc.description.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.	en_US
dc.language	eng	en_US
dc.relation.ispartof	Am J Hum Genet	en_US
dc.relation.isbasedon	10.1086/521953	en_US
dc.subject.classification	Genetics & Heredity	en_US
dc.subject.mesh	Pigment Epithelium of Eye	en_US
dc.subject.mesh	Chromosomes, Human	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Retinitis Pigmentosa	en_US
dc.subject.mesh	Ubiquitin-Protein Ligases	en_US
dc.subject.mesh	Neoplasm Proteins	en_US
dc.subject.mesh	Nuclear Proteins	en_US
dc.subject.mesh	Pedigree	en_US
dc.subject.mesh	DNA Mutational Analysis	en_US
dc.subject.mesh	Base Sequence	en_US
dc.subject.mesh	Genes, Dominant	en_US
dc.subject.mesh	Mutation	en_US
dc.subject.mesh	Exons	en_US
dc.subject.mesh	Molecular Sequence Data	en_US
dc.subject.mesh	Adolescent	en_US
dc.subject.mesh	Adult	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Child	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.title	Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy.	en_US
dc.type	Journal Article
utslib.citation.volume	5	en_US
utslib.citation.volume	81	en_US
utslib.location.activity	United States	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
utslib.copyright.status	closed_access
pubs.issue	5	en_US
pubs.publication-status	Published	en_US
pubs.volume	81	en_US

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/4753