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

Coats plus is a highly pleiotropicdisorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomeremaintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomericcapping complex. Consistent with the observation of shortened telomeresin an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomericmaintenance disorders comprising dyskeratosiscongenita, we observed shortened telomeresin 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 telomericintegrity.