TINF2, a Component of the Shelterin Telomere Protection Complex, Is Mutated in Dyskeratosis Congenita

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2008; 82(2):501-9. DOI: 10.1016/j.ajhg.2007.10.004
Source: PubMed


Patients with dyskeratosis congenita (DC), a heterogeneous inherited bone marrow failure syndrome, have abnormalities in telomere biology, including very short telomeres and germline mutations in DKC1, TERC, TERT, or NOP10, but approximately 60% of DC patients lack an identifiable mutation. With the very short telomere phenotype and a highly penetrant, rare disease model, a linkage scan was performed on a family with autosomal-dominant DC and no mutations in DKCI, TERC, or TERT. Evidence favoring linkage was found at 2p24 and 14q11.2, and this led to the identification of TINF2 (14q11.2) mutations, K280E, in the proband and her five affected relatives and TINF2 R282H in three additional unrelated DC probands, including one with Revesz syndrome; a fifth DC proband had a R282S mutation. TINF2 mutations were not present in unaffected relatives, DC probands with mutations in DKC1, TERC, or TERT or 298 control subjects. We demonstrate that a fifth gene, TINF2, is mutated in classical DC and, for the first time, in Revesz syndrome. This represents the first shelterin complex mutation linked to human disease and confirms the role of very short telomeres as a diagnostic test for DC.

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    • "H/ACA proteins, including dyskerin, NOP10, NHP2, and GAR1, recognize H/ACA-box sequences [6-8] and recruit TERC into a unique subnuclear organelle called Cajal body, which is crucial for assembly of telomerase components [9]. Mutations in the TERC gene as well as in other telomerase components cause accelerated telomere attrition, leading to disease: dyskeratosis congenita mainly in children [10-15], pulmonary fibrosis [16-18], liver cirrhosis [19], and bone marrow failure syndromes of adults (aplastic anemia, myelodysplastic syndromes (MDS), and others) [20-22]. "
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    ABSTRACT: Background Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease. Case presentation A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient’s TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father’s blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient’s leukocytes and contributed to the pathogenesis of bone marrow failure in our patient. Conclusion We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient’s hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment.
    BMC Medical Genetics 06/2014; 15(1):68. DOI:10.1186/1471-2350-15-68 · 2.08 Impact Factor
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    • "Autosomal dominant and recessive forms of this disease are due to mutations in hTERC and hTERT, respectively (Vulliamy et al., 2001, 2004), while X-linked DC is a result of mutations in Dyskerin (DC1), a small nuclear RNA–binding protein that interacts with TERC and is required for telomerase function (Mitchell et al., 1999). Mutations in the shelterin component TIN2 result in a very severe form of DC, with patients bearing very short telomeres and displaying premature BM failure as early as 10 years of age, even though telomerase function remains intact (Savage et al., 2008; Walne et al., 2008). These observations strongly implicate defects in telomere maintenance as a mechanism for disease formation and suggest that DC could arise not only from loss of telomerase activity but also from defects in the capping functions of the shelterin complex. "
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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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    • "For instance, progressive telomere shortening is directly implicated in replicative senescence, and reactivation of the telomerase represents one of the hallmarks of cancer cells (Shay & Wright, 2011). In addition, mutation and dysfunction of telomerase complex components (e.g., dyskerin) and telosome/shelterin subunits (e.g., TIN2) have been identified in diseases with premature aging phenotypes and predisposition to cancer (Heiss et al., 1998; Savage et al., 2008; Vulliamy et al., 2008; Walne et al., 2008; Zhong et al., 2011; Sasa et al., 2012). "
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    ABSTRACT: Telomeres are specialized structures at the ends of eukaryotic chromosomes that are important for maintaining genome stability and integrity. Telomere dysfunction has been linked to aging and cancer development. In mammalian cells, extensive studies have been carried out to illustrate how core telomeric proteins assemble on telomeres to recruit the telomerase and additional factors for telomere maintenance and protection. In comparison, how changes in growth signaling pathways impact telomeres and telomere-binding proteins remains largely unexplored. The phosphatidylinositol 3-kinase (PI3-K)/Akt (also known as PKB) pathway, one of the best characterized growth signaling cascades, regulates a variety of cellular function including cell proliferation, survival, metabolism, and DNA repair, and dysregulation of PI3-K/Akt signaling has been linked to aging and diseases such as cancer and diabetes. In this study, we provide evidence that the Akt signaling pathway plays an important role in telomere protection. Akt inhibition either by chemical inhibitors or small interfering RNAs induced telomere dysfunction. Furthermore, we found that TPP1 could homodimerize through its OB fold, a process that was dependent on the Akt kinase. Telomere damage and reduced TPP1 dimerization as a result of Akt inhibition was also accompanied by diminished recruitment of TPP1 and POT1 to the telomeres. Our findings highlight a previously unknown link between Akt signaling and telomere protection. This article is protected by copyright. All rights reserved.
    Aging cell 07/2013; 12(6). DOI:10.1111/acel.12137 · 6.34 Impact Factor
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