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: 29.65). 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.

  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 9.69 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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; DOI:10.1111/acel.12139 · 5.94 Impact Factor
  • Source
    • "In Arabidopsis, the absence of any one of the CST components leads to an inability to maintain apical meristems , physiologically manifesting in fused stems, aberrant organ development, and decreased fertility (Song et al. 2008; Surovtseva et al. 2009; KA Leehy et al., in prep.). Similarly, mutations within human CTC1 are the causative factor in certain types of Dyskeratosis congenita and Coats plus, severe genetic disorders characterized by premature death within stem cell niches (Levy et al. 2010; Anderson et al. 2012; Keller et al. 2012). The high incidence of chromosomal fusions in Arabidopsis CST mutants argues that genome instability underlies stem cell death and, in addition, a mechanism is in place to eliminate genetically defective cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Telomeres serve two vital functions: They act as a buffer against the end-replication problem, and they prevent chromosome ends from being recognized as double-strand DNA (dsDNA) breaks. These functions are orchestrated by the telomerase reverse transcriptase and a variety of telomere protein complexes. Here, we discuss our recent studies with Arabidopsis thaliana that uncovered a new and highly conserved telomere complex called CST (Cdc13/CTC1, STN1, TEN1). Formerly believed to be yeast specific, CST has now been identified as a key component of both plant and vertebrate telomeres, which is essential for genome integrity and stem cell viability. We also describe the unexpected discovery of alternative telomerase ribonucleoprotein complexes in Arabidopsis. Fueled by duplication and diversification of the telomerase RNA subunit and telomerase accessory proteins, these telomerase complexes act in concert to maintain genome stability. In addition to the canonical telomerase enzyme, one of two alternative telomerase ribonucleoprotein (RNP) complexes functions as a novel negative regulator of enzyme activity in response to genotoxic stress. These contributions highlight the immense potential of Arabidopsis in probing the depths of the chromosome end.
    Cold Spring Harbor Symposia on Quantitative Biology 03/2013; DOI:10.1101/sqb.2013.77.017053
Show more