Mutations in the TOPORS gene cause 1% of autosomal dominant retinitis pigmentosa

Abstract

Purpose: The purpose of this project was to determine if mutations, including large insertions or deletions, in the recently identified RP31 gene topoisomerase I-binding arginine-serine rich (RS) protein (TOPORS), cause an appreciable fraction of autosomal dominant retinitis pigmentosa (adRP).

Methods: An adRP cohort of 215 families was used to determine the frequency of TOPORS mutations. We looked for mutations in TOPORS by testing 89 probands from the cohort without mutations in other known adRP genes. Mutation detection was performed by fluorescent capillary sequencing and by multiplex ligation probe amplification.

Results: Two different TOPORS mutations, p.Glu808X and p.Arg857GlyfsX9, were each identified in one proband. Patients with these mutations exhibited clinical signs typical of advanced adRP. No large deletions or insertions of TOPORS were identified in our study.

Conclusions: Point mutations and small insertions or deletions in TOPORS cause approximately 1% of adRP. Large deletions or insertions of TOPORS are not an appreciable cause of adRP. Contrary to previous reports, no distinct clinical phenotype was seen in these patients.

Figure 1

Pedigrees of families with TOPORS mutations. A: This family has the p.Arg857GlyfsX9 (c.2569delA) mutation. B: RFS169. This family has the p.Glu808X (c.2422C>T) mutation. Circles indicate females; squares indicate males. Black filled symbols are affected individuals, open symbols are unaffected individuals, and the “Q” indicated an individual in New York who reports being asymptomatic. “E”s indicate individuals who had eye examination at either the Retina Foundation of the Southwest or the Jules Stein Eye Institute. “M”s indicate individuals for whom ophthalmic medical records were reviewed. Plus signs show individuals whose DNA tested positive for the family's mutation; minus signs are individuals whose DNA tested negative for the family's mutations.

Figure 2

Fundus photographs from RFS169. Right midpheripheral fundus (A) and right peripheral fundus (B) photographs from the 41-year-old sister of the proband from family RFS169. The midperiphery of both eyes contained numerous bone-spicule-like pigment deposits and the retinal arterioles were slightly narrowed by comparison to the veins. There was no evidence of a perivascular cuff of retinal pigment epithelium atrophy around the superior and inferior arcades in this family.

Figure 3

Frequency of autosomal dominant retinitis pigmentosa mutations found in the autosomal dominant retinitis pigmentosa cohort by gene. Gene abbreviations: rhodopsin (RHO); peripherin 2 (PRPH2); pre-mRNA processing factor 31 homolog (PRPF31); retinitis pigmentosa 1 (RP1); pre-mRNA processing factor 8 homolog (PRPF8); inosine monophosphate dehydrogenase 1 (IMPDH1); retinitis pigmentosa GTPase regulator (RPGR); nuclear receptor subfamily 2, group E, member 3 (NR2E3); pre-mRNA processing factor 3 homolog (PRPF3); topoisomerase I-binding arginine-serine rich gene (TOPORS); cone-rod otx-like photoreceptor homeobox transcription factor (CRX); retinal outer segment membrane protein 1 (ROM1). Testing identified mutations in 60% of our autosomal dominant retinitis pigmentosa cohort of 215 families. Mutations have yet to be identified in the remaining 40%.