TOPORS — TOPORS, topoisomerase I binding RS domain containing

The TOPORS gene provides instructions for making a protein that plays a crucial role in the health and maintenance of the retina, the light-sensitive tissue at the back of the eye. This protein acts like a cellular manager, helping to tag other proteins for recycling or modifying them so they can perform their specific jobs. In the retina, the TOPORS protein is especially important in the photoreceptor cells (the rods and cones that capture light). It helps maintain a tiny, bridge-like structure called the connecting cilium, which is essential for transporting vital materials within the cell. When there is a mutation or error in the TOPORS gene, the resulting protein may be abnormally short or not function correctly. This disrupts the delicate transport system in the photoreceptor cells, causing them to slowly deteriorate and die. For patients, this leads to a condition called retinitis pigmentosa (RP). The first symptom is usually night blindness, where it becomes difficult to see in dim light. Over time, patients experience a gradual loss of their side (peripheral) vision, which can eventually lead to "tunnel vision" and, in severe cases, legal blindness. TOPORS-related retinitis pigmentosa is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the mutated gene from one parent to develop the condition. Every child of an affected individual has a 50% chance of inheriting the mutated gene. While there is currently no cure for this condition, genetic testing can confirm the diagnosis, and regular eye exams can help manage symptoms and complications, such as cataracts or swelling in the retina. Researchers are actively exploring new treatments, including gene therapy, to help preserve vision in the future.

Gene description: Encodes a protein with E3 ubiquitin ligase activity, involved in protein degradation pathways.

Patient and family guide: The TOPORS gene provides instructions for making a protein that plays a crucial role in the health and maintenance of the retina, the light-sensitive tissue at the back of the eye. This protein acts like a cellular manager, helping to tag other proteins for recycling or modifying them so they can perform their specific jobs. In the retina, the TOPORS protein is especially important in the photoreceptor cells (the rods and cones that capture light). It helps maintain a tiny, bridge-like structure called the connecting cilium, which is essential for transporting vital materials within the cell. When there is a mutation or error in the TOPORS gene, the resulting protein may be abnormally short or not function correctly. This disrupts the delicate transport system in the photoreceptor cells, causing them to slowly deteriorate and die. For patients, this leads to a condition called retinitis pigmentosa (RP). The first symptom is usually night blindness, where it becomes difficult to see in dim light. Over time, patients experience a gradual loss of their side (peripheral) vision, which can eventually lead to "tunnel vision" and, in severe cases, legal blindness. TOPORS-related retinitis pigmentosa is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the mutated gene from one parent to develop the condition. Every child of an affected individual has a 50% chance of inheriting the mutated gene. While there is currently no cure for this condition, genetic testing can confirm the diagnosis, and regular eye exams can help manage symptoms and complications, such as cataracts or swelling in the retina. Researchers are actively exploring new treatments, including gene therapy, to help preserve vision in the future.

Gene function: TOPORS functions as an E3 ubiquitin ligase, mediating protein ubiquitination and subsequent degradation. In the retina, its role is thought to be critical in maintaining cellular homeostasis and protein quality control, and its disruption can lead to photoreceptor dysfunction and degeneration.

Protein structure: The TOPORS (Topoisomerase I-binding arginine/serine-rich) protein is a large nuclear and ciliary protein consisting of 1,045 amino acids. It is characterized by several distinct functional domains that enable its diverse cellular roles. At its N-terminus, TOPORS contains a RING-type zinc finger domain, which is essential for its E3 ubiquitin ligase activity, allowing it to interact with ubiquitin-conjugating enzymes (E2s) and transfer ubiquitin to target proteins. The central and C-terminal regions of the protein are rich in serine and arginine residues (RS domains), which are typically involved in protein-protein interactions and RNA processing. TOPORS also contains multiple sumoylation consensus sites, enabling its function as a SUMO1 E3 ligase. The protein undergoes various post-translational modifications, including phosphorylation, which regulate its activity and subcellular localization. In the retina, TOPORS localizes to the connecting cilium of photoreceptors, where it likely interacts with other ciliary proteins to form functional complexes necessary for intracellular transport.

Molecular function: TOPORS (Topoisomerase I-binding arginine/serine-rich protein) is a multifunctional protein that acts as both a ubiquitin E3 ligase and a SUMO1 E3 ligase. It plays a critical role in the post-translational modification of various target proteins, regulating their stability, localization, and activity. One of its well-characterized substrates is the tumor suppressor protein p53, which TOPORS ubiquitinates, leading to its proteasomal degradation. This dual ligase activity allows TOPORS to participate in diverse cellular processes, including DNA damage response, cell cycle regulation, and chromatin remodeling. In the context of the retina, TOPORS is localized to the connecting cilium and the basal body of photoreceptor cells. It is essential for the proper functioning of the primary cilium, a structure critical for the transport of proteins and lipids from the inner segment to the outer segment of the photoreceptors. TOPORS interacts with various ciliary and centrosomal proteins, facilitating the assembly and maintenance of the ciliary transition zone. Disruption of TOPORS function impairs this transport mechanism, leading to the accumulation of proteins in the inner segment, structural defects in the outer segment, and ultimately, photoreceptor cell death, which is the hallmark of retinitis pigmentosa.

Expression pattern: TOPORS is ubiquitously expressed in various human tissues, with particularly high expression levels in the testis and the retina. Within the retina, TOPORS is predominantly localized to the photoreceptor cells, specifically at the connecting cilium and the basal body complex, which are critical structures for the transport of proteins between the inner and outer segments of the photoreceptors. It is also expressed in the retinal pigment epithelium (RPE). During development, TOPORS expression is tightly regulated and plays a crucial role in the formation and maturation of the photoreceptor outer segments. The specific localization of TOPORS at the connecting cilium underscores its importance in the maintenance of photoreceptor structure and function, and explains why mutations in this gene lead to retinal degeneration.

Mutation spectrum: The mutation spectrum of TOPORS in retinitis pigmentosa is predominantly characterized by truncating variants, including nonsense mutations, frameshift deletions, and insertions. These mutations typically lead to premature stop codons and the production of a truncated, non-functional protein, or result in nonsense-mediated mRNA decay, leading to haploinsufficiency. Missense mutations are less common but have also been reported. A notable feature of TOPORS mutations is their clustering within a specific region of the gene, particularly affecting amino acid residues 807 to 867. This hotspot region is critical for the protein's function or stability. To date, several dozen pathogenic variants have been identified in the TOPORS gene, accounting for approximately 1% of all autosomal dominant retinitis pigmentosa cases. Large genomic rearrangements, such as whole-gene deletions or duplications, are rare.

Pathogenic variants: 1. p.Glu808Ter (c.2422G>T) - A nonsense mutation that leads to a premature stop codon, resulting in a truncated protein. It is a well-characterized cause of autosomal dominant retinitis pigmentosa. 2. p.Arg838Ter (c.2512C>T) - Another common nonsense mutation in the hotspot region, leading to premature truncation and associated with classic adRP symptoms. 3. p.Ser853Ter (c.2558C>G) - A truncating mutation that disrupts the C-terminal domain of the protein, leading to haploinsufficiency and retinal degeneration. 4. c.2556_2557del (p.Glu853fs) - A frameshift deletion that alters the reading frame and introduces a premature stop codon, frequently reported in adRP families. 5. p.Tyr825Ter (c.2474dup) - A duplication leading to a frameshift and premature truncation, classified as pathogenic and associated with adRP.

Clinical significance: Mutations in the TOPORS gene are a rare cause of autosomal dominant retinitis pigmentosa (adRP), accounting for approximately 1% of adRP cases. The clinical manifestation typically involves progressive night blindness (nyctalopia) starting in the first or second decade of life, followed by a gradual loss of peripheral vision, eventually leading to tunnel vision. The severity of the disease can vary significantly even among family members with the same mutation, suggesting the influence of genetic modifiers or environmental factors. A distinctive clinical feature often associated with TOPORS mutations is the presence of perivascular retinal pigment epithelium (RPE) atrophy, which can be observed during fundus examination. Patients may also develop cystoid macular edema (CME) and early-onset posterior subcapsular cataracts, which can further compromise central vision. The progression of the disease is generally slow, but most patients experience significant visual impairment by middle age.

Inheritance: Autosomal Recessive

Chromosomal location: 9p21.1

Genotype-phenotype correlations: Genotype-phenotype correlations in TOPORS-associated retinitis pigmentosa are complex and not fully understood due to the rarity of the condition. However, it has been observed that most pathogenic variants are truncating mutations (nonsense or frameshift) that cluster in a specific region of the protein, typically between amino acids 807 and 867. These mutations are thought to result in haploinsufficiency or a dominant-negative effect, leading to the disease phenotype. Despite the clustering of mutations, there is significant clinical variability among patients, even those carrying the same pathogenic variant. This variable expressivity suggests that other genetic or environmental factors may influence the severity and progression of the disease. For example, some patients may experience early-onset severe vision loss, while others may maintain useful vision well into adulthood. The presence of perivascular RPE atrophy is a consistent finding in many patients, but its extent and impact on vision can vary.

Research and therapeutic approaches: Currently, there are no FDA-approved targeted therapies specifically for TOPORS-associated retinitis pigmentosa. Management primarily focuses on supportive care, including the use of low-vision aids, orientation and mobility training, and regular monitoring for treatable complications such as cataracts and cystoid macular edema (CME). CME can often be managed with topical or oral carbonic anhydrase inhibitors (e.g., dorzolamide or acetazolamide). Vitamin A supplementation has been historically considered for some forms of RP, but its efficacy is debated and it must be used with caution. In the pipeline, gene therapy holds significant promise for inherited retinal diseases. While Luxturna (voretigene neparvovec-rzyl) is approved for RPE65-associated retinal dystrophy, gene therapy for TOPORS is still in the preclinical stages. Because TOPORS mutations typically cause disease through haploinsufficiency or a dominant-negative mechanism, therapeutic strategies may require either gene supplementation (to restore normal protein levels) or gene editing approaches like CRISPR/Cas9 to correct or silence the mutant allele. Additionally, neuroprotective agents and optogenetics are being explored broadly for RP to preserve remaining photoreceptors or restore light sensitivity to other retinal cells, regardless of the specific genetic mutation.

Diagnostic testing: Diagnosis of TOPORS-associated retinitis pigmentosa involves a combination of clinical evaluation and genetic testing. Clinical assessment typically includes a detailed family history, visual field testing, electroretinography (ERG) to measure photoreceptor function, and high-resolution retinal imaging such as optical coherence tomography (OCT) and fundus autofluorescence. Genetic testing is essential for a definitive diagnosis and is usually performed using targeted next-generation sequencing (NGS) panels that include TOPORS and other known IRD genes, or through whole exome sequencing (WES). Genetic counseling is a critical component of the diagnostic process. Since TOPORS mutations cause autosomal dominant retinitis pigmentosa, affected individuals have a 50% chance of passing the pathogenic variant to each of their children. Genetic counselors can help patients and their families understand the inheritance pattern, the variable expressivity of the disease, and the implications for family planning. They can also provide information on available resources, support groups, and potential participation in clinical trials.

Animal models: Zebrafish and mouse models have been instrumental in understanding TOPORS function. In zebrafish, topors knockdown or knockout models have demonstrated its essential role in retinal development and photoreceptor survival, with mutants showing defective outer segment formation and increased apoptosis. Mouse models, including Topors knockout mice, have revealed that the protein is crucial for normal retinal structure and function, with its absence leading to progressive photoreceptor degeneration that mimics the human retinitis pigmentosa phenotype. These models have highlighted the importance of TOPORS in maintaining the structural integrity of the connecting cilium and the proper transport of proteins to the outer segment.

Population genetics: Mutations in the TOPORS gene are a rare cause of autosomal dominant retinitis pigmentosa, accounting for approximately 1% of adRP cases globally. The carrier frequency in the general population is extremely low, reflecting the rarity of the condition. While TOPORS mutations have been identified in various ethnic groups, there is no strong evidence of a significant founder effect in most populations. However, specific variants may be more prevalent in certain isolated or consanguineous communities due to genetic drift. Large-scale population genomic databases, such as gnomAD, show that truncating variants in the TOPORS gene are highly constrained and rarely found in healthy individuals, supporting their high penetrance and pathogenicity in causing retinal disease.

Selected references: 1. Chakarova CF, et al. Mutations in TOPORS Cause Autosomal Dominant Retinitis Pigmentosa with Perivascular Retinal Pigment Epithelium Atrophy. Am J Hum Genet, 2007. PMID: 17924349 2. Bowne SJ, et al. Mutations in the TOPORS gene cause 1% of autosomal dominant retinitis pigmentosa. Mol Vis, 2008. PMID: 18509552 3. Chakarova CF, et al. TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein. Hum Mol Genet, 2011. PMID: 21149283 4. Rajendra R, et al. Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J Biol Chem, 2004. PMID: 15210701 5. Wang J, et al. Autosomal Dominant Retinitis Pigmentosa-Associated TOPORS Protein Truncating Variants Are Exclusively Located in the Region of Amino Acid Residues 807 to 867. Invest Ophthalmol Vis Sci, 2022. PMID: 35103768 6. Eid AT, et al. Autosomal Dominant Retinitis Pigmentosa Secondary to TOPORS Mutations: A Report of a Novel Mutation and Clinical Findings. J Clin Med, 2024. PMID: 38466014