Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, UK.
Nature Genetics (Impact Factor: 29.35). 03/2012; 44(3):338-42. DOI: 10.1038/ng.1084
Source: PubMed

ABSTRACT 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 observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.

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Available from: Michel Philippart, Sep 26, 2015
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    • "Revesz syndrome is also exceptionally rare, and is characterized by symptoms of HHS with the addition of exudative retinopathy (Kajtár and Méhes, 1994). Coats Plus syndrome has recently been linked to mutations in the CTC1 gene (Anderson et al., 2012), and patients with CTC1 mutation-derived Coats Plus syndrome may exhibit symptoms of HHS and Revesz syndrome, with the addition of cerebral calcifications. Despite these distinctions , cerebral calcifications and exudative retinopathy have been observed in patients with all three severe forms of DKC (Scheinfeld et al., 2007; Ramasubramanian and Shields, 2012). "
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    ABSTRACT: A constellation of related genetic diseases are caused by defects in the telomere maintenance machinery. These disorders, often referred to as telomeropathies, share symptoms and molecular mechanisms, and mounting evidence indicates they are points along a spectrum of disease. Several new causes of these disorders have been recently discovered, and a number of related syndromes may be unrecognized telomeropathies. Progress in the clinical understanding of telomeropathies has in turn driven progress in the basic science of telomere biology. In addition, the pattern of genetic anticipation in some telomeropathies generates thought-provoking questions about the way telomere length impacts the course of these diseases.
    The Journal of Cell Biology 05/2014; 205(3):289-99. DOI:10.1083/jcb.201401012 · 9.83 Impact Factor
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    • "Progressive telomere attrition in the absence of CTC1 leads to the formation of end-to-end chromosome fusions, culminating in complete BM failure and premature death (Gu et al., 2012). Critically shortened telomeres were also observed in some Coats Plus patients with phenotypes resembling DC, including those bearing the K242*/ R987W and R287*/C985del CTC1 mutations (Anderson et al., 2012; Keller et al., 2012). However, it was not clear whether all CTC1 mutations resulted in telomere shortening, because two reports failed to demonstrate any telomere shortening in patients bearing CTC1 mutations (V665G/L1142H mutations; Polvi et al., 2012; Walne et al., 2012). "
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    ABSTRACT: Coats plus is a rare recessive disorder characterized by intracranial calcifications, hematological abnormalities and retinal vascular defects. This disease results from mutations in CTC1, a member of the CTC1-STN1-TEN1 complex critical for telomere replication. Telomeres are specialized DNA/protein structures essential for the maintenance of genome stability. Several Coats plus patients display critically shortened telomeres, suggesting that telomere dysfunction plays an important role in disease pathogenesis. These patients inherit CTC1 mutations in a compound heterozygous manner, with one allele encoding a frameshift mutant and the other a missense mutant. How these mutations impact upon telomere function is unknown. We report here the first biochemical characterization of human CTC1 mutations. We found that all CTC1 frameshift mutations generated truncated or unstable protein products, none of which were able to form a complex with STN1-TEN1 on telomeres, resulting in progressive telomere shortening and formation of fused chromosomes. Missense mutations behaved more like the wild type protein, are able to form the CST complex at telomeres but their expression levels are often repressed by the frameshift mutants. Our results also demonstrate for the first time that CTC1 mutations promote telomere dysfunction by decreasing the stability of STN1 to reduce its ability to interact with DNA Polα, and highlight a previously unknown mechanism to induce telomere dysfunction. This article is protected by copyright. All rights reserved.
    Aging cell 07/2013; 12(6). DOI:10.1111/acel.12139 · 6.34 Impact Factor
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    • "Linnankivi and co-workers [6] believe that Coats plus syndrome and LCC are manifestations of the same disease spectrum, termed cerebroretinal microangiopathy with calcifications and cysts. Recently, identification of biallelic mutations in the CTC1 gene in the vast majority of patients with Coats plus syndrome but in none with LCC provides strong evidence that the two conditions are genetically distinct entities [9,10]. Anderson et al. [9] argued that the difference between LCC and Coasts plus is whether there are extra-neurological problems. "
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    ABSTRACT: Introduction Leukoencephalopathy, brain calcifications and cysts, known as Labrune syndrome, is a rare syndrome. The etiology is unknown; in some cases it is difficult to differentiate from Coats plus syndrome and diagnosed as cerebroretinal microangiopathy with calcifications and cysts. We present the case of a patient with adult leukoencephalopathy, brain calcifications and cysts and discuss recently described entities in view of the relevant literature. Case presentation A previously healthy 19-year-old Chinese man presented with weakness of his right limbs that rapidly worsened over a short interval. Computed tomography and magnetic resonance imaging showed numerous low-density cysts, calcifications, and abnormal signal change of white matter. A visual field examination showed irregular visual field defects in both eyes. A neuro-ophthalmologic examination did not find evidence of Coats retinopathy. A larger excisional biopsy was carried out and a diagnosis of leukoencephalopathy, brain calcifications and cysts was confirmed. Conclusions We present an example of adult-onset leukoencephalopathy, brain calcifications and cysts and have expanded the clinical spectrum of features associated with this syndrome. Previous reports have not, to the best of our knowledge, previously reported visual field defects. Based on the latest findings, we believe that leukoencephalopathy, brain calcifications and cysts and Coats plus syndrome are genetically distinct entities.
    Journal of Medical Case Reports 06/2013; 7(1):151. DOI:10.1186/1752-1947-7-151
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