RESUMEN
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.
Asunto(s)
Genes Dominantes , Mutación/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Epitelio Pigmentado Ocular/irrigación sanguínea , Epitelio Pigmentado Ocular/patología , Retinitis Pigmentosa/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Cromosomas Humanos , Análisis Mutacional de ADN , Exones/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Linaje , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Retinitis pigmentosa (RP) is a debilitating disease of the retina affecting approximately 1.5 million people worldwide. RP shows remarkable heterogeneity both clinically and genetically, with more than 40 genetic loci implicated, 12 of which account for the autosomal dominant form (adRP) of inheritance. We have recently identified a French Canadian family that presents with early onset adRP. After exclusion of all known loci for adRP, a genome-wide search established firm linkage with a marker from the short arm of chromosome 9 (LOD score of 6.3 at recombination fraction theta=0). The linked region is flanked by markers D9S285 and D9S1874, corresponding to a genetic distance of 31 cM, in the region 9p22-p13.