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.

Genotype and Phenotype Studies in Autosomal Dominant Retinitis Pigmentosa (adRP) of the French Canadian Founder Population

“…11,12 The human homolog of yeast pre-mRNA splicing gene (PRPF31; MIM# 606419) 1% to 8% 13,14 ; small nuclear ribonucleoprotein 200 kDa (U5) (SNRNP200; MIM# 601664) has a prevalence at least 4.2% in the Caucasian population, and topoisomerase I-binding RS protein (TOPORS; MIM# 609507) with prevalence of 1% in European and US cohorts. 13,15 The rest of the adRP genes have a much lower prevalence in the adRP cases. The most common adRP causing genes with their geographic prevalence are listed in the Table 1.…”

“…A cohort of 60 index patients with adRP collected in the French Canadian population underwent direct sequencing of [9][10][11] 3%-9% European ancestry Retinitis pigmentosa -1 (RP1; MIM# 603937) 11,12 0%-10% Various geographic origins Human homolog of yeast pre-mRNA splicing gene (PRPF31; MIM# 606419) 13,14 1%-8% USA and Europe Small nuclear ribonucleoprotein 200kDa (U5) (SNRNP200; MIM# 601664) 13,15 4.2% USA and Europe Topoisomerase I-binding RS protein (TOPORS; MIM# 609507) 13,15 1% USA and Europe adRP of the French Canadian Founder Population IOVS j December 2015 j Vol. 56 j No.…”

The role of primary cilia in the development and disease of the retina

“…Examples include the TOPORS protein, loss of which is associated with failure of OS formation in zebrafish, 33 and retinitis pigmentosa (RP), a hereditary retinal degeneration in humans. 34 OFD1 is a distal centriole protein that regulates the length of centrioles 35 and ciliary axonemes. 36 Mutations in OFD1 cause oro-facial-digital syndrome, non-syndromic RP, and RP as a feature of Joubert syndrome (JBTS).…”

Molecular Genetics of Charcot-Marie-Tooth Disease: From Genes to Genomes

“…blind mutational screenings of all genes present in a given linkage region) have allowed the discovery of mutations in genes that a priori were not considered as prime candidates (e.g. [Chakarova et al, 2007]). As mentioned above, strategies to prioritize candidate genes based on gene function (if known) and on similarity with or functional relation to genes involved in the same disease [Dryja, 1990[Dryja, , 1997 may not always be successful as structurally and functionally diverse gene products might cause the same or a similar phenotype.…”