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

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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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Figure 1: Features of Coats plus.
Figure 2: Schematic representation of the human CTC1 gene.
Figure 3: Telomere length analysis in subsets of leukocytes as measured by automated multicolor flow-FISH.

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We are very grateful to the affected families for their involvement in our research. Y.J.C. acknowledges the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre. This work has received support from the Great Ormond Street Hospital Children's Charity and from the Newlife Foundation. We thank the NHLBI Grand Opportunity (GO) Exome Sequencing Project and acknowledge its ongoing studies that produced and provided exome variant calls for comparison, including the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). We also thank G. Forte for organizing courier delivery of patient materials.

Author information

B.H.A. and J.O. performed exome sequencing. B.H.A., M.S., G.I.R. and E.M.J. were responsible for Sanger sequencing. J. Mayer, S.S.B. and J.E.D. undertook analysis of the exome sequence data. J.E.U. and S.B.D. performed SNP analyses. J.H.L. was responsible for neuroradiological phenotyping. G.M.B. and E.O.L. performed the telomeric length analysis. S.M. and J. Muter assessed γH2AX positivity. S.C.L. analyzed CTC1 structural domains. G.I.R. and G.C.M.B. provided critical input into project development and manuscript preparation. Y.J.C. designed and supervised the project and wrote the manuscript with the support of P.R.K. All other authors identified subjects with Coats plus and/or Labrune syndrome and performed related clinical and laboratory studies. Phenotypic overlap with dyskeratosis congenita was originally appreciated by J.L.T. and J.B.P.S. at the time of the first clinical description of Coats plus.

Correspondence to Yanick J Crow.

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