TOPORS – Autosomal Dominant Retinitis Pigmentosa

The TOPORS gene encodes Topoisomerase I-binding RS protein, a dual E3 ubiquitin/SUMO ligase. Heterozygous variants in TOPORS have been implicated in autosomal dominant retinitis pigmentosa, presenting with early-onset nyctalopia, progressive peripheral visual field constriction, and variable macular pathology ([PMID:38592336]). Most pathogenic alleles cluster in exon 3, affecting the C-terminal region and suggesting a haploinsufficiency mechanism. Electroretinography often reveals diminished rod responses preceding central vision loss. Clinical severity correlates with variant class, with truncating mutations resulting in more rapid functional decline.

In a rural Appalachian cohort, seven affected women from three unrelated families harbored heterozygous TOPORS variants, including a novel nonsense mutation c.2431C>T (p.Gln811Ter) that segregated in a mother–daughter pair and caused early severe night blindness, cataract, and full-thickness macular hole requiring repair ([PMID:38592336]). Five additional patients carried previously reported truncating or missense changes, confirming phenotypic consistency across pedigrees. Segregation analysis in these families identified at least 2 affected relatives, establishing cosegregation of truncating alleles with disease.

A founder population study in French Canadians screened 60 adRP pedigrees and identified TOPORS mutations in three families (12.5% of solved cases), including the recurrent missense c.2666A>G (p.His889Arg), with complete segregation in available relatives ([PMID:26720483]). The variant spectrum in this founder cohort expanded to four novel missense changes, underscoring population-specific allele frequencies and confirming AD inheritance.

A systematic review combining our cohort with previous reports summarized 39 TOPORS alleles, of which 25 (64.1%) are truncating and 12 (34.3%) are missense. Most map to the terminal half of exon 3 and demonstrate genotype–phenotype correlation: truncating alleles associate with poorer preserved central vision than missense variants ([PMID:35254173]). Night blindness (HP:0000662) is the most common presenting symptom, with ERG changes detectable early in disease.

Functional assays reveal that phosphorylation of serine 98 regulates TOPORS ubiquitin ligase activity: a phosphomimetic S98D mutant increases ubiquitination and E2 binding, while a phosphodeficient S98A does not, without affecting SUMOylation or nuclear localization ([PMID:19053840]). These data support a loss-of-function mechanism whereby pathogenic TOPORS alleles disrupt ubiquitin-mediated photoreceptor homeostasis.

Integration of genetic and experimental evidence supports a Strong clinical validity classification: multiple unrelated probands (10) with heterozygous truncating/missense variants, segregation across pedigrees, and concordant functional data. Haploinsufficiency emerges as the primary pathogenic mechanism in TOPORS-related adRP. No conflicting reports have been documented. Key take-home: heterozygous TOPORS variants are a validated and actionable cause of autosomal dominant retinitis pigmentosa, meriting inclusion in diagnostic gene panels.

References

• Journal of clinical medicine • 2024 • Autosomal Dominant Retinitis Pigmentosa Secondary to TOPORS Mutations: A Report of a Novel Mutation and Clinical Findings. PMID:38592336
• Investigative ophthalmology & visual science • 2015 • Genotype and Phenotype Studies in Autosomal Dominant Retinitis Pigmentosa (adRP) of the French Canadian Founder Population. PMID:26720483
• Human Genetics • 2022 • To identify TOPORS mutations in patients with retinitis pigmentosa (RP) and summarize the genotypes and phenotypes of TOPORS. PMID:35254173
• Biochemistry • 2008 • Identification of phosphorylation sites of TOPORS and a role for serine 98 in the regulation of ubiquitin but not SUMO E3 ligase activity. PMID:19053840

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