Alternative titles; symbols
HGNC Approved Gene Symbol: CTC1
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38) : 17:8,224,815-8,248,056 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | Cerebroretinal microangiopathy with calcifications and cysts | 612199 | Autosomal recessive | 3 |
CTC1 and STN1 (613128) are subunits of an alpha accessory factor (AAF) that stimulates the activity of DNA polymerase-alpha-primase (see 176636), the enzyme that initiates DNA replication (Casteel et al., 2009). CTC1 also functions in a telomere-associated complex with STN1 and TEN1 (613130) (Miyake et al., 2009).
Casteel et al. (2009) cloned mouse Aaf132, which encodes a deduced 1,211-amino acid protein. By database analysis, they identified human AAF132. The human and mouse proteins share 69% identity. Northern blot analysis detected variable Aaf132 expression in several mouse tissues, with highest expression in testis. Endogenous Aaf132 protein had an apparent molecular mass of 132 kD by SDS-PAGE. Aaf44 (Stn1) and Aaf132 colocalized in nuclei of transfected synchronized HeLa cells, with exclusion from nucleoli. The 2 proteins colocalized with PCNA (176740), presumably within DNA replication foci.
By searching databases for homologs of mouse Ctc1, Miyake et al. (2009) identified human CTC1. The deduced 1,217-amino acid human protein has 2 oligonucleotide/oligosaccharide-binding (OB) folds in its N-terminal half and a third OB fold near the C terminus. OB folds are typically found in proteins that bind single-stranded DNA (ssDNA). Immunohistochemical analysis and FISH revealed that CTC1 colocalized with telomeric DNA.
Hartz (2009) mapped the CTC1 gene to chromosome 17p13.1 based on an alignment of the CTC1 sequence (GenBank AK025823) with the genomic sequence (GRCh37).
Casteel et al. (2009) mapped the mouse Ctc1 gene to chromosome 11.
Cryoelectron Microscopy
The CTC1-STN1 (613128)-TEN1 (613130) complex, also known as the CST complex, is essential for telomere maintenance and resolution of stalled replication forks genomewide. Lim et al. (2020) reported the 3.0-angstrom cryoelectron microscopy structure of human CST bound to telomeric single-stranded DNA, which assembles as a decameric supercomplex. The atomic model of the 134-kD CTC1 subunit, built almost entirely de novo, revealed the overall architecture of CST and the DNA-binding anchor site. The carboxyl-terminal domain of STN1 interacts with CTC1 at 2 separate docking sites, allowing allosteric mediation of CST decamer assembly. Furthermore, ssDNA appears to staple 2 monomers to nucleate decamer assembly. CTC1 has stronger structural similarity to replication protein A (RPA; see 179835) than the expected similarity to yeast Cdc13. The decameric structure suggested that CST can organize ssDNA analogously to the nucleosome's organization of double-stranded DNA.
Using immunoprecipitation analysis, Casteel et al. (2009) showed that epitope-tagged mouse Aaf44 and Aaf132 interacted in transfected HEK293 cells. Expression of Aaf44 appeared to stabilize the Aaf132 protein. When expressed individually, Aaf44 and Aaf132 weakly bound single-stranded oligo(dC), but when expressed together, they showed strong ssDNA binding. When coexpressed, Aaf44 and Aaf132 formed an AAF complex that stimulated DNA primase activity by calf or human polymerase-alpha-primase on a poly(dT) template.
Using Western blot analysis of coimmunoprecipitated proteins and yeast 2-hybrid assays, Miyake et al. (2009) showed that CTC1 interacted with STN1 and TEN1 in a complex, which the authors called the CST complex. STN1 interacted with both CTC1 and TEN1, but CTC1 and TEN1 did not show significant interaction. The CST complex immunoprecipitated telomeric DNA, but not Alu repeat DNA, from HeLa cells. Only a fraction of telomeres associated with the CST complex, and association of the CST complex with telomeres did not vary during the cell cycle. The CST complex, but not its individual components, bound ssDNA with high affinity and in a sequence-independent manner. The CST complex appeared to protect telomeres independently of POT1 (606478). Knockdown studies suggested that the CST complex and POT1 play redundant roles in telomere protection.
Chen et al. (2012) demonstrated that the human CST complex, implicated in telomere protection and DNA metabolism, inhibits telomerase (see 602322) activity through primer sequestration and physical interaction with the POT1-TPP1 (609377) telomerase processivity factor. CST competes with POT1-TPP1 for telomeric DNA, and CST-telomeric-DNA binding increases during late S/G2 phase only on telomerase action, coinciding with telomerase shut-off. Depletion of CST allows excessive telomerase activity, promoting telomere elongation. Chen et al. (2012) proposed that through binding of the telomerase-extended telomere, CST limits telomerase action at individual telomeres to approximately one binding and extension event per cell cycle. The authors suggested that their findings defined the sequence of events that occur to first enable and then terminate telomerase-mediated telomere elongation.
In affected individuals from 10 families with Coats plus syndrome, which is a form of cerebroretinal microangiopathy with calcifications and cysts (CRMCC1; 612199), Anderson et al. (2012) identified 14 different mutations in the CTC1 gene (see, e.g., 613129.0001-613129.0005). The first mutations were found by exome sequencing of a sib pair. All patients were compound heterozygous for 2 mutations. Three patients were found to have shortened telomere lengths in white blood cells, and heterozygous family members had telomere lengths at the lower range of normal. Cell lines derived from 2 patients showed an increase in spontaneous H2AX histone (601772)-positive cells, indicating an ongoing DNA damage response. The phenotype was somewhat variable, but most patients had intrauterine growth retardation, intracranial calcifications, leukoencephalopathy, early-onset retinal changes, early-onset bone fractures, and gastrointestinal ectasia. Some had hair, nail, and skin changes, and/or anemia. Noting the role of CTC1 in DNA replication, Anderson et al. (2012) concluded that mutations in the CTC1 gene may disrupt DNA metabolism and telomere integrity. Sequencing excluded mutations in the CTC1 gene in 21 probands with Labrune syndrome, defined as intracranial calcifications and leukoencephalopathy without extraneurologic features, suggesting that these 2 disorders may not be allelic, even though they show phenotypic overlap.
Polvi et al. (2012) identified compound heterozygous mutations in the CTC1 gene (see, e.g., 613129.0006-613129.0011) in 13 of 15 patients with cerebroretinal microangiopathy with calcifications and cysts. The mutations were found by whole-exome sequencing in 4 apparently unrelated Finnish patients, followed by Sanger sequencing of the CTC1 gene in 11 additional patients from 10 families. Ten of the 15 patients had previously been reported (see, e.g., Linnankivi et al., 2006 and Briggs et al., 2008). A total of 11 mutations were found, 2 of which were recurrent (V665G, 613129.0006 and 2831delC, 613129.0007). Ten of the 12 families carried a missense mutation on 1 allele and a truncating mutation on the other allele. Only 1 patient carried 2 in-frame deletions, likely resulting in a protein product with altered functional properties; this patient had few extracranial manifestations. Since no patient carried 2 truncating mutations, it appeared likely that such a combination would be lethal in utero. CTC1 mutations were found in all patients with childhood onset of the disorder and with retinal involvement. Two of 3 patients with later onset and lack of clinical retinal anomalies did not carry CTC1 mutations; these 2 patients did not have systemic findings. There were no differences in telomere lengths in patients with CTC1 mutations compared to controls, suggesting that telomere integrity is not severely compromised in this disorder.
Functional Effects of CTC1 Mutations
Gu and Chang (2013) performed biochemical characterization of human CTC1 mutations involved in Coats plus telomere disease. They found that all CTC1 frameshift mutations generated truncated or unstable protein products that could not form CST complexes on telomeres, leading to progressive telomere shortening and formation of fused chromosomes. Missense mutations resulted in proteins that could form CST complexes, but their expression levels were often repressed by the frameshift mutants. CTC1 mutations promoted telomere dysfunction by decreasing the stability of STN1 and reducing the ability of STN1 to interact with DNA polymerase-alpha (POLA; see 312040). Gu and Chang (2013) proposed that failure of STN1 to interact with POLA would make inactivating STN1 mutations incompatible with survival.
In 2 Scottish sisters and an unrelated English patient, all with Coats plus syndrome (CRMCC1; 612199), Anderson et al. (2012) identified compound heterozygosity for 2 mutations in the CTC1 gene: a 4-bp deletion (724_727delAAAG) in exon 5, resulting in a frameshift and premature termination, and a 2959C-T transition in exon 18, resulting in an arg987-to-trp (R987W; 613129.0002) substitution. The missense mutation affected a residue well-conserved among mammals, and neither mutation was found in 1,730 controls. The patients had previously been reported by Briggs et al. (2008). All had intrauterine growth retardation, intracranial calcifications, leukoencephalopathy, early-onset retinal changes, and gastrointestinal ectasia. The sisters both had gray hair, translucent skin, and dystrophic nails, and the English patient had anemia. One of the sisters and the English patient had early-onset bone fractures. The 2 sisters died in their early twenties of gastrointestinal bleeding. One of the patients was found to have shortened telomere lengths in white blood cells, and each heterozygous parent had telomere lengths at the lower range of normal.
Keller et al. (2012) reported an 18-year-old girl who was compound heterozygous for 724_727delAAAG and a 3-bp deletion (c.2954_2956delGTT; 613129.0012) in the CTC1 gene. The patient presented at age 15 years with classic features of dyskeratosis congenita (see, e.g., 127550), including bone marrow failure, abnormalities in skin pigmentation, nail dysplasia, and graying hair. She also had short stature, osteopenia, decreased pulmonary function, and blurry vision associated with sheathed vessels and microaneurysm formation in the retina. Brain MRI showed calcifications in the right thalamus, and telomeres were shortened significantly. Neurologic function was normal. Patient fibroblasts showed a defect in outgrowth as well as rapid senescence compared to controls. Keller et al. (2012) noted that both CTC1 mutations had been reported in patients with Coats plus syndrome, suggesting that Coats plus syndrome and DKC show phenotypic and genetic overlap, consistent with a telomere-related disease.
For discussion of the arg987-to-trp (R987W) mutation in the CTC1 gene that was found in compound heterozygous state in patients with Coats plus syndrome (CRMCC1; 612199) by Anderson et al. (2012), see 613129.0001.
In a 28-year-old English woman with Coats plus syndrome (CRMCC1; 612199), Anderson et al. (2012) identified compound heterozygosity for 2 mutations in the CTC1 gene: a 2611G-A transition in exon 15, resulting in a val871-to-met (V871M) substitution, and a 4-bp deletion (724_727delAAAG; 613129.0001). The missense mutation, which affects a residue that is well-conserved among mammals, was not found in 1,730 controls. The patient had intrauterine growth retardation, intracranial calcifications, leukoencephalopathy, early-onset retinal changes, thin hair, dystrophic nails, anemia, early-onset bone fractures, absent thumbs, and gastrointestinal ectasia. She died of pulmonary fibrosis at age 28.
In 2 sibs, of English and Italian ancestry, with Coats plus syndrome (CRMCC1; 612199), Anderson et al. (2012) identified compound heterozygosity for 2 mutations in the CTC1 gene: a 775G-A transition in exon 5, resulting in a val259-to-met (V259M) substitution, and a 2518C-T transition in exon 15, resulting in an arg840-to-trp (R840W; 613129.0005) substitution. Both mutations affected residues well-conserved among mammals, and were not found in 1,730 controls. The patients had previously been reported by Briggs et al. (2008). Both had intrauterine growth retardation, intracranial calcifications, leukoencephalopathy, early-onset retinal changes, and early-onset bone fractures. One had anemia and gastrointestinal ectasia. Both died of neurologic complications in their teens.
For discussion of the arg840-to-trp (R840W) mutation in the CTC1 gene that was found in compound heterozygous state in patients with Coats plus syndrome (CRMCC1; 612199) by Anderson et al. (2012), see 613129.0004.
In 7 unrelated patients with cerebroretinal microangiopathy with calcifications and cysts (CRMCC1; 612199), Polvi et al. (2012) identified compound heterozygosity for 2 mutations in the CTC1 gene. All were heterozygous for a 1994T-G transversion in exon 12, resulting in a val665-to-gly (V665G) substitution. The pathogenic mechanism of this mutation was unclear because it does not affect a known functional domain. Four of the patients carried a 1-bp deletion (2831delC; 613129.0007) in exon 17, resulting in a frameshift and premature termination, on the second allele. The V665G and 2831delC mutations were identified by whole-exome sequencing. One patient had a 2-bp indel in exon 22 (3425_3426delTCinsAT; 613129.0008) on the other allele; this mutation was predicted to result in a leu1142-to-his (L1142H) substitution. Another patient had a 3583C-T transition in exon 23 on the other allele, predicted to result in an arg1195-to-ter (R1195X; 613129.0009) substitution. The seventh patient had a 680C-T transition in exon 5 on the other allele, resulting in an ala227-to-val (A227V; 613129.0010) substitution. The A227V substitution affects the first OB-fold domain and may interfere with DNA binding. Patients with the V665G mutation on 1 allele had early onset of the disorder, between birth and 1.5 years of age. Features included intrauterine growth retardation, brain calcifications, leukoencephalopathy, and variable neurologic features, including spasticity, ataxia, dystonia, and cognitive decline. All had retinal anomalies of some sort, mostly telangiectasia. More variable features included gastrointestinal bleeding, sparse hair, anemia, and thrombocytopenia. Four had died by age 20 years; 3 were alive at the time of the report.
For discussion of the 1-bp deletion in the CTC1 gene (2831delC) that was found in compound heterozygous state in patients with cerebroretinal microangiopathy with calcifications and cysts (CRMCC1; 612199) by Polvi et al. (2012), see 613129.0006.
For discussion of the leu1142-to-his (L1142H) mutation in the CTC1 gene that was found in compound heterozygous state in a patient with cerebroretinal microangiopathy with calcifications and cysts (CRMCC1; 612199) by Polvi et al. (2012), see 613129.0006.
For discussion of the arg1195-to-ter (R1195X) mutation in the CTC1 gene that was found in compound heterozygous state in a patient with cerebroretinal microangiopathy with calcifications and cysts (CRMCC1; 612199) by Polvi et al. (2012), see 613129.0006.
In 2 sibs with cerebroretinal microangiopathy with calcifications and cysts (CRMCC1; 612199), Polvi et al. (2012) identified compound heterozygosity for 2 mutations in the CTC1 gene: a 680C-T transition in exon 5, resulting in an ala227-to-val (A227V) substitution, and a 1-bp deletion in exon 6 (1058delC; 613129.0011), resulting in a frameshift and premature termination. The A227V substitution affects the first OB-fold domain and may interfere with DNA binding. The patients had originally been reported by Linnankivi et al. (2006). Both had intrauterine growth retardation. At ages 1 and 5 years, respectively, they were found to have brain calcifications and leukoencephalopathy. Neurologic features included spasticity, seizures, dystonia, and cognitive decline. Both had retinal telangiectasia, gastrointestinal bleeding, and osteopenia. Other features included sparse hair, anemia, and thrombocytopenia. They died at ages 22 and 16 years, respectively.
An unrelated patient with CRMCC reported by Polvi et al. (2012) was compound heterozygous for A227V and V665G (613129.0006).
For discussion of the 1-bp deletion in the CTC1 gene (1058delC) that was found in compound heterozygous state in patients with cerebroretinal microangiopathy with calcifications and cysts (CRMCC1; 612199) by Polvi et al. (2012), see 613129.0010.
In a 20-year-old man with cerebroretinal microangiopathy with calcifications and cysts (CRMCC1; 612199), Anderson et al. (2012) identified compound heterozygosity for 2 mutations in the CTC1 gene: an in-frame 3-bp deletion (2954_2956delGTT) in exon 18, resulting in a deletion of cys985, and an 859C-T transition in exon 6, resulting in an arg287-to-ter (R287X; 613129.0013) substitution. The patient, who had previously been reported by Crow et al. (2004) as having Coats plus syndrome, had intrauterine growth retardation, intracranial calcifications, leukoencephalopathy, retinal changes, dystrophic nails, and shortened telomere lengths.
For discussion of the 3-bp deletion in the CTC1 gene that was found in compound heterozygous state in a patient with CRMCC who had classic features of dyskeratosis congenita (see, e.g., 127550) by Keller et al. (2012), see 613129.0001.
For discussion of the arg287-to-ter (R287X) mutation in the CTC1 gene that was found in compound heterozygous state in a patient with cerebroretinal microangiopathy with calcifications and cysts (CRMCC1; 612199) by Anderson et al. (2012), see 613129.0012.
Anderson, B. H., Kasher, P. R., Mayer, J., Szynkiewicz, M., Jenkinson, E. M., Bhaskar, S. S., Urquhart, J. E., Daly, S. B., Dickerson, J. E., O'Sullivan, J., Leibundgut, E. O., Muter, J., and 52 others. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nature Genet. 44: 338-342, 2012. [PubMed: 22267198] [Full Text: https://doi.org/10.1038/ng.1084]
Briggs, T. A., Abdel-Salam, G. M. H., Balicki, M., Baxter, P., Bertini, E., Bishop, N., Browne, B. H., Chitayat, D., Chong, W. K., Eid, M. M., Halliday, W., Hughes, I., and 12 others. Cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Am. J. Med. Genet. 146A: 182-190, 2008. [PubMed: 18076099] [Full Text: https://doi.org/10.1002/ajmg.a.32080]
Casteel, D. E., Zhuang, S., Zeng, Y., Perrino, F. W., Boss, G. R., Goulian, M., Pilz, R. B. A DNA polymerase-alpha-primase cofactor with homology to replication protein A-32 regulates DNA replication in mammalian cells. J. Biol. Chem. 284: 5807-5818, 2009. [PubMed: 19119139] [Full Text: https://doi.org/10.1074/jbc.M807593200]
Chen, L.-Y., Redon, S., Lingner, J. The human CST complex is a terminator of telomerase activity. Nature 488: 540-544, 2012. [PubMed: 22763445] [Full Text: https://doi.org/10.1038/nature11269]
Crow, Y. J., McMenamin, J., Haenggeli, C. A., Hadley, D. M., Tirupathi, S., Treacy, E. P., Zuberi, S. M., Browne, B. H., Tolmie, J. L., Stephenson, J. B. P. Coats' plus: a progressive familial syndrome of bilateral Coats' disease, characteristic cerebral calcification, leukoencephalopathy, slow pre- and post-natal linear growth and defects of bone marrow and integument. Neuropediatrics 35: 10-19, 2004. [PubMed: 15002047] [Full Text: https://doi.org/10.1055/s-2003-43552]
Gu, P., Chang, S. Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus. Aging Cell 12: 1100-1109, 2013. [PubMed: 23869908] [Full Text: https://doi.org/10.1111/acel.12139]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/20/2009.
Keller, R. B., Gagne, K. E., Usmani, G. N., Asdourian, G. K., Williams, D. A., Hofmann, I., Agarwal, S. CTC1 mutations in a patient with dyskeratosis congenita. Pediat. Blood Cancer 59: 311-314, 2012. [PubMed: 22532422] [Full Text: https://doi.org/10.1002/pbc.24193]
Lim, C. J., Barbour, A. T., Zaug, A. J., Goodrich, K. J., McKay, A. E., Wuttke, D. S., Cech, T. R. The structure of human CST reveals a decameric assembly bound to telomeric DNA. Science 368: 1081-1085, 2020. [PubMed: 32499435] [Full Text: https://doi.org/10.1126/science.aaz9649]
Linnankivi, T., Valanne, L., Paetau, A., Alafuzoff, I., Hakumaki, J. M., Kivela, T., Lonnqvist, T., Makitie, O., Paakkonen, L., Vainionpaa, L., Vanninen, R., Herva, R., Pihko, H. Cerebroretinal microangiopathy with calcifications and cysts. Neurology 67: 1437-1443, 2006. [PubMed: 16943371] [Full Text: https://doi.org/10.1212/01.wnl.0000236999.63933.b0]
Miyake, Y., Nakamura, M., Nabetani, A., Shimamura, S., Tamura, M., Yonehara, S., Saito, M., Ishikawa, F. RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Molec. Cell 36: 193-206, 2009. [PubMed: 19854130] [Full Text: https://doi.org/10.1016/j.molcel.2009.08.009]
Polvi, A., Linnankivi, T., Kivela, T., Herva, R., Keating, J. P., Makitie, O., Pareyson, D., Vainionpaa, L., Lahtinen, J., Hovatta, I., Pihko, H., Lehesjoki, A.-E. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am. J. Hum. Genet. 90: 540-549, 2012. [PubMed: 22387016] [Full Text: https://doi.org/10.1016/j.ajhg.2012.02.002]