CTC1 – Dyskeratosis Congenita

CTC1 encodes the conserved telomere maintenance component 1, a key member of the CST (CTC1–STN1–TEN1) complex required for telomere C-strand fill-in and replication. Autosomal recessive biallelic CTC1 variants underlie dyskeratosis congenita (MONDO:0015780), a telomere biology disorder characterized by mucocutaneous features and bone marrow failure.

Genetic evidence supports a strong association: at least 8 unrelated probands have been reported with biallelic CTC1 variants and dyskeratosis congenita (1 proband [PMID:22532422]; 6 probands [PMID:22899577]; 1 proband [PMID:32543263]). Disease segregation is limited by small family sizes and lack of extensive relative genotyping. The inheritance is consistently autosomal recessive.

The variant spectrum includes one recurrent missense and multiple truncating alleles. Reported variant types are missense, in-frame deletions, and frameshifts. A representative pathogenic allele is c.2959C>T (p.Arg987Trp), which disrupts CST assembly and telomere association.

Functional assays in biochemical and cellular models demonstrate that CTC1 frameshift mutations produce unstable or truncated proteins unable to bind STN1–TEN1, leading to progressive telomere shortening and chromosome fusions ([PMID:23869908]). Missense mutations impair CST complex formation, telomerase regulation, and DNA polymerase α recruitment in vitro and in vivo ([PMID:24115768]). iPSC-derived models from patients recapitulate telomere length heterogeneity, DNA damage signaling, and chromosomal instability ([PMID:36011306]).

There is no substantive conflicting evidence disputing CTC1’s role in dyskeratosis congenita. Multi-patient screens and case series have consistently identified biallelic CTC1 variants in affected individuals.

Integration of genetic and functional data confirms that loss of CTC1 function via compound heterozygous or homozygous variants leads to telomere replication defects and the clinical triad of dyskeratosis congenita. Genetic testing for CTC1 mutations informs diagnosis and early intervention for marrow failure.

Key Take-home: Biallelic CTC1 mutations cause autosomal recessive dyskeratosis congenita through disruption of CST complex–mediated telomere maintenance, supporting its utility in molecular diagnosis and management.

References

• Pediatric Blood & Cancer | 2012 | CTC1 Mutations in a patient with dyskeratosis congenita. PMID:22532422
• Haematologica | 2013 | Mutations in the telomere capping complex in bone marrow failure and related syndromes. PMID:22899577
• Ophthalmic Genetics | 2020 | A unique case of coats plus syndrome and dyskeratosis congenita in a patient with CTC1 mutations. PMID:32543263
• Aging Cell | 2013 | Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus. PMID:23869908
• Genes & Development | 2013 | Molecular basis of telomere syndrome caused by CTC1 mutations. PMID:24115768
• Genes | 2022 | Patient-Derived iPSCs Reveal Evidence of Telomere Instability and DNA Repair Deficiency in Coats Plus Syndrome. PMID:36011306

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