Mutations in TOPORS Cause Autosomal Dominant Retinitis Pigmentosa with Perivascular Retinal Pigment Epithelium Atrophy
| Autor: | Kinga M. Bujakowska, Mai M. Abd El-Aziz, Shomi S. Bhattacharya, James S. Friedman, Bernd Wissinger, Wendy A. Bickmore, Christina Chakarova, Cécilia Maubaret, Brotati Veraitch, Eberhart Zrenner, Myrto Papaioannou, Torsten Theis, Christian P. Hamel, Andreas Gal, Peter M. G. Munro, Amna Z. Shah, Hemant Khanna, De Quincy C. Prescott, Anand Swaroop, Irma Lopez, Karl Matter, Valeria Marigo, Naushin Waseem, Sunil K. Parapuram, Robert K. Koenekoop, Chris P. Ponting |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Adolescent Ubiquitin-Protein Ligases DNA Mutational Analysis Molecular Sequence Data Locus (genetics) Biology 03 medical and health sciences Exon 0302 clinical medicine Mutant protein Report Retinitis pigmentosa Genetics medicine Chromosomes Human Humans Genetics(clinical) Nuclear protein Child Pigment Epithelium of Eye Gene Genetics (clinical) Genes Dominant 030304 developmental biology Genetics & Heredity 0303 health sciences retinitis pigmentosa topoisomerase I-binding RS protein Base Sequence Nuclear Proteins Exons Middle Aged medicine.disease Phenotype Neoplasm Proteins Pedigree Mutation 030221 ophthalmology & optometry Female Haploinsufficiency Retinitis Pigmentosa |
| Zdroj: | The American Journal of Human Genetics. 81:1098-1103 |
| ISSN: | 0002-9297 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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