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

Abstract

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

Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

“…Genetic variants of Stn1 are associated with increased telomere length in leukocytes [7] and expressing a deletion mutant of Stn1 in cancer cells causes telomere lengthening [5], suggesting that Stn1 may be involved in telomere length regulation. Recently, mutations in Ctc1 have been isolated from patients with telomere disorder dyskeratosis congenita (DC) and patients with Coats Plus (CP) syndrome, a complex genetic disease clinically related to DC [8][9][10]. Shortened telomeres were observed in both CP and DC patients carrying Ctc1 mutations [8,10], suggesting that the underlying cause for CP may be related to defective telomere maintenance induced by Ctc1 mutations.…”

“…Recently, mutations in Ctc1 have been isolated from patients with telomere disorder dyskeratosis congenita (DC) and patients with Coats Plus (CP) syndrome, a complex genetic disease clinically related to DC [8][9][10]. Shortened telomeres were observed in both CP and DC patients carrying Ctc1 mutations [8,10], suggesting that the underlying cause for CP may be related to defective telomere maintenance induced by Ctc1 mutations. Though it has been shown that transient depletion of Ctc1 or Stn1 in HeLa leads to telomere instability [3,4], the precise role of human CST complex is largely unknown.…”

Mutations in the telomere capping complex in bone marrow failure and related syndromes

“…This rare multisystem disorder is thought to encompass both Coats plus and leukoencephalopathy with calcifications and cysts (LCC). 9,10 The key characteristics of this disorder include intracranial calcifications and leukoencephalopathy, retinal vasculature abnormalities, skeletal abnormalities and recurrent gastrointestinal hemorrhage. Dystrophic nails, sparse hair and abnormal skin pigmentation have occasionally been observed in such patients.…”

CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length

“…Coats plus patients are compound heterozygous for two different CTC1 mutations, with one allele harboring a frameshift mutation and the other a missense variant (Anderson et al., 2012; Keller et al., 2012; Polvi et al., 2012; Walne et al., 2013). Previous analysis of the human CTC1 L1142H mutation relied on transient expression of the mutant in HT1080 cells bearing wild‐type (WT) CTC1 alleles, making it difficult to understand the in vivo effects of this mutation (Chen et al., 2013).…”

“…Missense mutations in the human CTC1 gene cause Coats plus (CP), a rare autosomal recessive disorder characterized by retinal telangiectasia, intracranial calcifications, osteopenia, and gastrointestinal bleeding (Anderson et al., 2012; Polvi et al., 2012; Walne et al., 2013). While some CP patients possess very short telomeres and have phenotypes resembling those patients with Dyskeratosis congenita (DC), suggesting that telomere maintenance is also functionally impaired in these patients, telomere lengths in other CP patients are not markedly reduced (Polvi et al., 2012).…”