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Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observ...
Citations
... Patients may also present with pancytopenia, osteopenia, sparse hair, and fragile, dysplastic nails. 7 Ophthalmic findings in CPS are traditionally evaluated via fundus examination and fluorescein angiography (FA). There is limited literature on mild ocular phenotypes of CPS. ...
Coats plus syndrome (CPS), also referred to as cerebroretinal microangiopathy with calcifications and cysts (CMCC), is a rare autosomal recessive disease that primarily targets the microvasculature of the retina, brain, bones, and gastrointestinal system. This study reports the case of a 24-year-old female patient who was initially diagnosed with familial exudative vitreoretinopathy (FEVR) and was lost to follow-up. The patient underwent multimodal retinal imaging, including ultra-widefield swept-source optical coherence tomography angiography (UWF SS-OCTA) (DREAM OCT, Intalight). Examination revealed areas of peripheral avascular retina with limited exudation and telangiectasis. Ultra-widefield SS-OCTA provided a detailed view of the peripheral retinal changes, including temporal retinal ischemia, vessel tortuosity, dilated intercapillary spaces, and vessel shunting. Genetic testing was positive for CTC1 mutation and the diagnosis of CPS was made. Mild phenotypes of Coats plus can mimic FEVR and there is a need to maintain a level of suspicion in patients with any systemic symptoms. Ultra-widefield OCTA can be used to assess peripheral avascularity and telangiectasias to aid in the diagnosis and management.
[Ophthalmic Surg Lasers Imaging Retina 2025;56:XX–XX.]
... Coats plus disease is a rare severe TBD that is associated with bilateral exudative retinopathy 'Coats-like' in addition to multiple systemic manifestations including intracranial calcification, intrauterine growth restriction, short stature, pulmonary fibrosis, bone marrow failure and others [89,90]. CTC1 mutations cause Coats plus disease [91]. CTC1 encodes conserved telomere maintenance component 1 and, as the name suggests, is responsible for maintaining telomeres [91]. ...
... CTC1 mutations cause Coats plus disease [91]. CTC1 encodes conserved telomere maintenance component 1 and, as the name suggests, is responsible for maintaining telomeres [91]. Clinically, Coats plus disease resembles Coats disease with peripheral non-perfusion, telangiectasia and vascular leakage on fluorescein angiography ( Figure 5) in addition to exudation [89,90]. ...
Hereditary vitreoretinopathies (HVRs), also known as hereditary vitreoretinal degenerations comprise a heterogeneous group of inherited disorders of the retina and vitreous, collectively and variably characterised by vitreal abnormalities, such as fibrillary condensations, liquefaction or membranes, as well as peripheral retinal abnormalities, vascular changes in some, an increased risk of retinal detachment and early‐onset cataract formation. The pathology often involves the vitreoretinal interface in some, while the major underlying abnormality is vascular in others. Recent advances in molecular diagnosis and identification of the responsible genes and have improved our understanding of the pathogenesis, risks and management of the HVRs. Clinically, HVRs can be classified according to the presence or absence of skeletal or other systemic abnormalities, retinal dysfunction or retinal vascular abnormalities [2]. There are some discrepancies in the literature regarding which diseases are included under the overarching term ‘hereditary vitreoretinopathies’. Conditions such as Stickler syndrome, Wagner syndrome and familial exudative vitreoretinopathy are generally included, while others such as autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) and autosomal dominant vitreoretinochoroidapathy (ADVIRC) may not. In this review, we will discuss some historical aspects, the molecular pathogenesis, clinical features and management of diseases and syndromes commonly considered as HVRs.
... Mutations affecting the CST gene CTC1 in humans cause Coats plus syndrome, an autosomal recessive disorder characterized by retinal telangiectasia, intracranial calcifications, osteopenia, gastrointestinal bleeding and, in severe cases, normocytic anaemia reflecting a degree of bone marrow failure 33 . Similarly, hematopoietic stem cell (HSC) exhaustion characterizes mice homozygous for Ctc1 gene deletions, leading to complete bone marrow failure and perinatal lethality 34 . ...
Tumor suppressor p53-binding protein 1 (53BP1) regulates DNA end joining in lymphocytes, diversifying immune antigen receptors. This involves nucleosome-bound 53BP1 at DNA double-stranded breaks (DSBs) recruiting Rap1-interacting factor 1 homolog (RIF1) and shieldin, a poorly understood DNA-binding complex. The 53BP1–RIF1–shieldin axis is pathological in BRCA1-mutated cancers, blocking homologous recombination (HR) and driving illegitimate nonhomologous end joining (NHEJ). However, how this axis regulates DNA end joining and HR suppression remains unresolved. We investigated shieldin and its interplay with the Ctc1–Stn1–Ten1 (CST) complex, which was recently implicated downstream of 53BP1. Immunophenotypically, mice lacking shieldin or CST are equivalent, with class-switch recombination coreliant on both complexes. Ataxia-telangiectasia mutated kinase-dependent DNA damage signaling underpins this cooperation, inducing physical interactions between these complexes that reveal shieldin as a DSB-responsive CST adaptor. Furthermore, DNA polymerase ζ functions downstream of shieldin, establishing DNA fill-in synthesis as the physiological function of shieldin–CST. Lastly, we demonstrate that 53BP1 suppresses HR and promotes NHEJ in BRCA1-deficient mice and cells independently of shieldin. These findings showcase the versatility of the 53BP1 pathway, achieved through the collaboration of chromatin-bound 53BP1 complexes and DNA end-processing effector proteins.
... Briefly, we used available Mosdepth 73 coverage files available across 482,839 WGS samples, which given the scale were calculated using a 'quantized' strategy that merges adjacent bases if they fall in the same coverage bin. Overall, four read depth bins were selected ((0-9), (10)(11)(12)(13)(14)(15)(16)(17)(18)(19), and (50+)). To compute overall coverage, we assumed that the coverage for a given base was the median of the read depth for that bin. ...
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1 . Notably, 16% of these genes are known drivers of clonal hematopoiesis—an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2 -mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.
... While initially DKC was considered an appropriate term for all telomere-related diseases, it later became clear that on the one hand side, certain pediatric forms such as the Revesz syndrome, the Hoyeraal-Hreidarsson syndrome, or the Coats plus syndrome are characterized by a strikingly more severe phenotype and earlier disease onset clearly distinct from classical DKC [48,64,78]. On the other hand, adult-onset forms of TBDs sometimes only manifest themselves beyond 40 years of age, often lacking a skin phenotype and displaying distinct and highly variable organ system manifestations from classical DKC [36,45]. ...
... Consequently, in parallel to the identification of a growing number of disease-causing genes, there was also a change in nomenclature [7,44]. For instance, some patients with a Coats plus syndrome harbor a pathogenic variant in a gene important for telomere maintenance and show a TBD phenotype, but do not have shorter TL [43,48,61]. This led to the change in terminology away from the term telomeropathy or telomere disease to the currently used term TBD [17,43]. ...
... Abnormalities of the skeletal system are often accompanied by impaired bone healing. The leukodystrophy can lead to a progressive cognitive decline [48]. Also, anemia and thrombocytopenia (with or without BMF) are common symptoms. ...
b> Background: Telomeres are the end-capping structures of all eukaryotic chromosomes thereby protecting the genome from damage and degradation. During the aging process, telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis. Premature aging due to critically short telomere length (TL) can also result from pathogenic germline variants in the telomerase complex or related genes that typically counteract replicative telomere shortening in germline and certain somatic cell populations, e.g., hematopoetic stem cells. Inherited diseases that result in altered telomere maintenance are summarized under the term telomere biology disorder (TBD). Summary: Since TL both reflects but more importantly restricts the replicative capacity of various human tissues, a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin). Consequently, altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis. Key Messages: The recognition of a potential congenital origin in approximately 10% of adult patients with clinical BMF is of utmost importance for the proper diagnosis, appropriate patient and family counseling, to prevent the use of inefficient treatment and to avoid therapy-related toxicities including appropriate donor selection when patients have to undergo stem cell transplantation from related donors. This review summarizes the current state of knowledge about TBDs with particular focus on the clinical manifestation patterns in children (termed early onset TBD) compared to adults (late-onset TBD) including typical treatment- and disease course-related complications as well as their prognosis and adequate therapy. Thereby, it aims to raise awareness for a disease group that is currently still highly underdiagnosed particularly when it first manifests itself in adulthood.
... Together, these processes shorten the telomeric C-strand by approximately 76 nt per population doubling in HCT116 cells. In keeping with the critical role of CST-Polα-primase in solving the second end-replication problem, defects in this pathway lead to telomere biology disorders-predominantly Coats plus syndrome 40 and, more rarely, dyskeratosis congenita (reviewed in ref. 21). It was proposed that CST-Polα-primase evolved in the last eukaryotic common ancester (or its Asgard archaeal ancestor) to maintain the 5′ ends of linear chromosomes 21,25 . ...
Telomerase adds G-rich telomeric repeats to the 3′ ends of telomeres¹, counteracting telomere shortening caused by loss of telomeric 3′ overhangs during leading-strand DNA synthesis (‘the end-replication problem’²). Here we report a second end-replication problem that originates from the incomplete duplication of the C-rich telomeric repeat strand (C-strand) by lagging-strand DNA synthesis. This problem is resolved by fill-in synthesis mediated by polymerase α-primase bound to Ctc1–Stn1–Ten1 (CST–Polα-primase). In vitro, priming for lagging-strand DNA replication does not occur on the 3′ overhang and lagging-strand synthesis stops in a zone of approximately 150 nucleotides (nt) more than 26 nt from the end of the template. Consistent with the in vitro data, lagging-end telomeres of cells lacking CST–Polα-primase lost 50–60 nt of telomeric CCCTAA repeats per population doubling. The C-strands of leading-end telomeres shortened by around 100 nt per population doubling, reflecting the generation of 3′ overhangs through resection. The measured overall C-strand shortening in the absence of CST–Polα-primase fill-in is consistent with the combined effects of incomplete lagging-strand synthesis and 5′ resection at the leading ends. We conclude that canonical DNA replication creates two telomere end-replication problems that require telomerase to maintain the G-rich strand and CST–Polα-primase to maintain the C-strand.
... The complex of CST proteins consists of three proteins-a telomeric DNA-binding protein, an oligonucleotide/oligosaccharide-binding folding protein 1 (STN1), and a telomere length-regulating protein (TEN1) [29]. The CST complex is responsible for the replication of telomeric DNA, promoting C-chain synthesis, and involved in regulating the telomere length [30][31][32][33]. Disruption of the CST complex results in the fragility of non-telomeric GC-rich repeat sequences, which is observed in the case of chromosome breakdown [34]. ...
Background:
The interaction between environmental and genetic factors that influence eye growth, regulated by vision, contributes to the development and progression of myopia. This dynamic interaction significantly contributes to the multifaceted development and progression of myopia, a prevalent ocular condition. Our study delves into the associations between ZNF676 and CTC1 gene polymorphisms and their impact on the relative leukocyte telomere length (relative LTL) in myopia, as well as its degree. By unravelling these underpinnings in conjunction with environmental influences, we aim to enhance our understanding of the complex mechanisms that drive the onset and severity of myopia.
Methods:
This study included patients with myopia and ophthalmologically healthy subjects. DNA was extracted from peripheral venous blood by the salting out method. Genotyping of ZNF676 rs412658 and CTC1 rs3027234, as well as the measurement of relative LTL, were conducted using a real-time polymerase chain reaction method (RT-PCR). The data obtained were statistically analyzed using the "IBM SPSS Statistics 29.0" software program.
Results:
The results show that myopic patients who are homozygous for the rs3027234 rare allele genotype of the CTC1 gene have statistically significantly shorter relative LTL compared to patients with the CC and CT genotypes. Also, men with the CTC1 rs3027234 TT genotype have statistically significantly longer leukocyte telomeres than women with the same genotype. The respective median (IQR) of the relative LTL for women and men is 0.280 (0.463) vs. 0.696 (0.440), with a p-value of 0.027. The myopia group with the ZNF676 rs412658 CC genotype has statistically significantly shorter leukocyte telomeres than the control group with the same genotype (age ≤ 29), and the p-value is 0.011. Also, the myopia group with the ZNF676 rs412658 CT and CTC1 rs3027234 CT genotypes have statistically significantly longer leukocyte telomeres than the control group with the same genotypes (age > 29), with p-values that are, respectively, 0.016 and 0.012. The evaluation of the genotype distributions of the polymorphisms in the myopia patients showed that ZNF676 rs412658 CT genotype carriers have 4-fold decreased odds of high myopia occurrence (OR = 0.250; CI: 0.076-0.826; p = 0.023). Also, the evaluation of the allele distributions of the polymorphism under the additive genetic model in the myopia group showed that the ZNF676 rs412658 T allele was associated with similar odds of high myopia (OR = 0.269; 95% CI: 0.090-0.807; p = 0.019). The comprehensive p-value, assessing the relative LTL of subjects across the different levels of myopia, signifies a statistical difference in the relative LTL among individuals with varying degrees of myopia. There was a statistically significant difference in relative LTL between mild and moderate myopia degrees (0.819 (1.983) vs. 0.083 (0.930), p = 0.007).
Conclusions:
CTC1 rs3027234 TT may be considered a protective genotype for telomere shortening in men, while the overall telomere shortening might be linked to the worse myopia degree. The ZNF676 rs412658 T allele may protect against a high myopia occurrence.
... PCNA-Pol δ then elongates the RNA-DNA primer until the C strand is fully synthesised [82,83,96]. The importance of the process described above is underline by human disease such as Coats plus syndrome having mutations in CST subunits 11 [156,157]. Recent findings suggest that the CST-Pol α complex solves an until recently little recognised second telomere end-replication problem since a lack of CST-Pol α yields not only shortening of the lagging strand at telomeres but also a resection of the leading strand DNA in the next round of DNA replication [150]. ...
The initiation reactions of DNA synthesis are central processes during human chromosomal DNA replication. They are separated into two main processes: the initiation events at replication origins, the start of the leading strand synthesis for each replicon, and the numerous initiation events taking place during lagging strand DNA synthesis. In addition, a third mechanism is the re-initiation of DNA synthesis after replication fork stalling, which takes place when DNA lesions hinder the progression of DNA synthesis. The initiation of leading strand synthesis at replication origin is regulated at multiple levels, from the origin recognition to the assembly and activation of replicative helicase, the Cdc45-MCM2-7-GINS (CMG) complex. In addition, the multiple interactions of the CMG complex with the eukaryotic replicative DNA polymerases such as DNA polymerase α-primase (Pol α), DNA polymerase δ and ε at replication forks play pivotal roles in the mechanism of initiation reactions including the initiation of signalling unperturbed and stalled replication forks, ‘replication stress’ events, via ATR (ATM-Rad 3-related protein kinase). All these processes are essential for the accurate transfer of the cells’ genetic information to their daughters. Failures and dysfunctions in these processes gives rise to genome instability followed by genetic diseases including cancer. Thus, in their review ‘Hallmarks of Cancer: New Dimensions‘ Hanahan and Weinberg (2022) called genome instability a fundamental function in the development process of cancer cells. In recent years, the understanding of the initiation processes and mechanisms of human DNA replication has made substantial progress at all levels which will be discussed in the review.
... The CST complex binds to single-stranded (ss) DNA and ss-ds DNA junctions 30,31 . Loss-of-function mutations in CTC1 and STN1 cause two complex genetic diseases Coats plus and Dyskeratosis congenita [32][33][34][35][36][37][38] . Moreover, CST has been implicated in tumor development, as STN1 variants are associated with various types of cancer [39][40][41][42][43][44] , and STN1 deficiency promotes colorectal cancer development in young adult mice 45 . ...
Keeping replication fork stable is essential for safeguarding genome integrity; hence, its protection is highly regulated. The CTC1-STN1-TEN1 (CST) complex protects stalled forks from aberrant MRE11-mediated nascent strand DNA degradation (NSD). However, the activation mechanism for CST at forks is unknown. Here, we report that STN1 is phosphorylated in its intrinsic disordered region. Loss of STN1 phosphorylation reduces the replication stress-induced STN1 localization to stalled forks, elevates NSD, increases MRE11 access to stalled forks, and decreases RAD51 localization at forks, leading to increased genome instability under perturbed DNA replication condition. STN1 is phosphorylated by both the ATR-CHK1 and the calcium-sensing kinase CaMKK2 in response to hydroxyurea/aphidicolin treatment or elevated cytosolic calcium concentration. Cancer-associated STN1 variants impair STN1 phosphorylation, conferring inability of fork protection. Collectively, our study uncovers that CaMKK2 and ATR-CHK1 target STN1 to enable its fork protective function, and suggests an important role of STN1 phosphorylation in cancer development.
... and it consists of 23 exons, spanning approximately 23.2 kilobases. In 2012, Anderson et al. described that variants of CTC1 were responsible for an autosomal recessive pleomorphic disorder named Coats plus syndrome, which featured intracranial calcifications, leukodystrophy, brain cysts, retinal telangiectasia and exudate extraneurologic manifestations [8]. Since then, a spectrum of phenotypes, including bone marrow failure, colorectal cancer and dyskeratosis congenita, have also been detected in patients with CTC1 mutations [9][10][11]. ...
... At present, a total of 51 mutations have been reported in patients, and most of them were identified in Coats plus syndrome patients or cerebroretinal microangiopathy with calcifications and cysts. Only four variants have been detected in patients with ILDs [8,12,13]. Here, we identified a novel mutation (NM_025099: p.Gly131Arg) in CTC1 in a family with IPF. Our study may expand the mutation spectrum of CTC1 and further prove that mutations in CTC1 may lead to ILDs. ...
... CTC1 mutations were first identified in Coat Plus and dyskeratosis congenita [8,24], two types of autosomal recessive disorders that are associated with telomere maintenance defects. In 2012, Anderson et al. first identified compound heterozygous variation (c.724_727delAAAG and c.2611G > A) of CTC1 in a young female who died from pulmonary fibrosis at the age of 28 and presented with dystrophic nails, thin hair, fractures, anemia, and gastrointestinal ectasia [8]. ...
Interstitial lung diseases (ILDs), or diffuse pulmonary lung disease, are a subset of lung diseases that primarily affect lung alveoli and the space around interstitial tissue and bronchioles. It clinically manifests as progressive dyspnea, and patients often exhibit a varied decrease in pulmonary diffusion function. Recently, variants in telomere biology-related genes have been identified as genetic lesions of ILDs. Here, we enrolled 82 patients with interstitial pneumonia from 2017 to 2021 in our hospital to explore the candidate gene mutations of these patients via whole-exome sequencing. After data filtering, a novel heterozygous mutation (NM_025099: p.Gly131Arg) of CTC1 was identified in two affected family members. As a component of CST (CTC1-STN1-TEN1) complex, CTC1 is responsible for maintaining telomeric structure integrity and has also been identified as a candidate gene for IPF, a special kind of chronic ILD with insidious onset. Simultaneously, real-time PCR revealed that two affected family members presented with short telomere lengths, which further confirmed the effect of the mutation in the CTC1 gene. Our study not only expanded the mutation spectrum of CTC1 and provided epidemiological data on ILDs caused by CTC1 mutations but also further confirmed the relationship between heterozygous mutations in CTC1 and ILDs, which may further contribute to understanding the mechanisms underlying ILDs.
