CTC1 Mutations in a patient with dyskeratosis congenita

Division of Hematology/Oncology, Stem Cell Program, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Pediatric Blood & Cancer (Impact Factor: 2.39). 08/2012; 59(2):311-4. DOI: 10.1002/pbc.24193
Source: PubMed

ABSTRACT Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome caused by mutations in seven genes involved in telomere biology, with approximately 50% of cases remaining genetically uncharacterized. We report a patient with classic DC carrying a compound heterozygous mutation in the CTC1 (conserved telomere maintenance component 1) gene, which has recently implicated in the pleiotropic syndrome Coats plus. This report confirms a molecular link between DC and Coats plus and expands the genotype-phenotype complexity observed in telomere-related genetic disorders.

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Available from: Rachel Beth Keller, Feb 04, 2015
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    • "Mice deficient in CTC1 show rapid C-strand loss, leading to bone marrow failure (Gu et al., 2012). Mutations in CTC1 have been identified in Coats Plus syndrome (Anderson et al., 2012; Keller et al., 2012; Polvi et al., 2012; Walne et al., 2013a). "
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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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    • "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. "
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    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; 77. DOI:10.1101/sqb.2013.77.017053
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