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

• Published in: Nature genetics Vol. 44; no. 3; pp. 338 - 342
• Main Authors: Anderson, Beverley H, Kasher, Paul R, Mayer, Josephine, Szynkiewicz, Marcin, Jenkinson, Emma M, Bhaskar, Sanjeev S, Urquhart, Jill E, Daly, Sarah B, Dickerson, Jonathan E, O'Sullivan, James, Leibundgut, Elisabeth Oppliger, Muter, Joanne, Abdel-Salem, Ghada M H, Babul-Hirji, Riyana, Baxter, Peter, Berger, Andrea, Bonafé, Luisa, Brunstom-Hernandez, Janice E, Buckard, Johannes A, Chitayat, David, Chong, Wui K, Cordelli, Duccio M, Ferreira, Patrick, Fluss, Joel, Forrest, Ewan H, Franzoni, Emilio, Garone, Caterina, Hammans, Simon R, Houge, Gunnar, Hughes, Imelda, Jacquemont, Sebastien, Jeannet, Pierre-Yves, Jefferson, Rosalind J, Kumar, Ram, Kutschke, Georg, Lundberg, Staffan, Lourenço, Charles M, Mehta, Ramesh, Naidu, Sakkubai, Nischal, Ken K, Nunes, Luís, Õunap, Katrin, Philippart, Michel, Prabhakar, Prab, Risen, Sarah R, Schiffmann, Raphael, Soh, Calvin, Stephenson, John B P, Stewart, Helen, Stone, Jon, Tolmie, John L, van der Knaap, Marjo S, Vieira, Jose P, Vilain, Catheline N, Wakeling, Emma L, Wermenbol, Vanessa, Whitney, Andrea, Lovell, Simon C, Meyer, Stefan, Livingston, John H, Baerlocher, Gabriela M, Black, Graeme C M, Rice, Gillian I, Crow, Yanick J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2012; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/727/2000; 631/80/103/560; Abnormalities, Multiple - genetics; Agriculture; Animal Genetics and Genomics; Arabidopsis; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedical research; Biomedicine; Cancer Research; Cell cycle; Cysts; Deoxyribonucleic acid; DNA; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gastrointestinal tract; Gene Function; Gene mutations; Genetic disorders; Genetic Predisposition to Disease - genetics; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Health aspects; Histones - metabolism; Human Genetics; letter; Medical research; Molecular Sequence Data; Mutation; Physiological aspects; Proteins; Retinal Telangiectasis - genetics; Retinal Telangiectasis - pathology; Sequence Analysis, DNA - methods; Siblings; Single nucleotide polymorphisms; Telomerase; Telomere - pathology; Telomere-Binding Proteins - genetics; Telomeres; Womens health; Yeasts; United Kingdom; Telomere; Mutation
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.1084

Yanick Crow and colleagues show that mutations in
CTC1
, which encodes a homolog of a yeast telomere maintenance protein, cause Coats plus, a highly pleiotropic disorder sharing phenotypic overlap with dyskeratosis congenita and other disorders of telomere maintenance.
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.