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An emerging role for the conserved telomere component 1 (CTC1) in human genetic disease

D yskeratosis congenita (DC) is a telomere-mediated disorder defined by a triad of mucocutaneous features: Skin hyperpigmentation, oral leukoplakia, and nail dystrophy. The majority of patients suffer morbidity and mortaily due to bone marrow failure, pulmonary fibrosis, or cancer. DC falls on a spectrum of telomere syndromes which have variable severity and age of onset [1]. These disorders collectively share the short telomere molecular defect as a pathogenic mechanism. Because in these patients the defect is germline, although one disease presentation may predominate, telomere syndromes have overlapping phenotypes, and subclinical disease in secondary sites is relevant to both diagnostic and treatment decisions [1]. In infancy and early childhood, telomere-mediated disease is recognized in Hoyeraal–Hreidarsson syndrome which is characterized by developmental delay and intracranial calcifications. Revesz syndrome, which also manifests in early childhood, is defined by severe developmental delay, intracranial calcifications, and exudative retinopathy. Affected patients share features with DC including bone marrow failure and, as the disease progresses, often acquire the classic features of DC in late childhood. In adults, telomere-mediated disease presents as isolated or syndromic clustering of bone marrow failure, pulmonary fibrosis, and liver cirrhosis [1]. The extent of telomere shortness determines the severity of disease with affected infants and children having the most severe telomere shortening defects [1]. Seven genes have been implicated in telomere-related phenotypes (including DC) [2], and all function as essential components of the telomerase enzyme or the telomere pathway. Mutations in four genes account for the majority of DC cases: DKC1, hTERT, hTR, and TINF2. More rarely, mutations in NHP2, NOP10, and TCAB1 can be identified. In approximately half of DC cases, the genetic basis remains uncharacterized. Recently, mutations in CTC1, the conserved telomere component 1, another gene involved in telomere maintenance were shown to cause Coats plus syndrome (also known as cerebroretinal microangiopathy with calcifications and cysts or CRMCC) [3,4]. Coats plus is a rare neurological disorder characterized by bilateral retinal exudative retinopathy (Coats disease) and a distinctive pattern of intracranial calcifications and cysts [5]. Patients also develop extra-neuronal phenotypes including premature hair graying, anemia, and osteoporosis. Because the latter features also affect DC patients, it has been long recognized that Coats plus might share a common disease mechanism with DC [5]. Using exome capture and massive parallel sequencing, Anderson et al. [3] identified biallelic mutations in CTC1 in 9 of 10 families with the Coats plus. Supporting a possible role for telomere shortening in Coats plus pathogenesis, Anderson et al. [3] showed that affected individuals have age-adjusted lymphocyte telomere length below the 1st percentile. This range is predictive of inherited defects in telomere maintenance, and this observation has raised the question as to whether the Coats plus phenotype might be another manifestation of the telomere syndrome spectrum. In another study, Polvi et al. reported CTC mutations in Coats plus patients, but using a different telomere length measurement technique failed to detect a telomere length defect [4]. A case report in this issue of Pediatric Blood & Cancer adds another layer to defining the role of CTC1 in human disease and telomere biology [6]. Keller et al. report identifying biallelic CTC1 mutations in a patient with typical features of a primary telomere disorder. The patient was 16 years old and had classic mucocutaneous DC features, bone marrow failure, and very short telomere length. Although this patient had no neurological or eyerelated symptoms, she was found to have intracranial calcifications as well as non-specific vascular retinal changes. Notably, the CTC1 variants she carried are identical to those previously identified in Coats plus patients. The CTC1 gene was recently identified as one member of a protein complex originally termed DNA polymerase-a accessory factor (AAF) involved in single strand DNA binding in an RPAlike complex [7]. CTC1 forms a complex with STN1 and TEN1, now known as the CST complex, and appears to function as an ortholog to the telomere end protection complex in yeast also termed CST [8,9]. Studies in plants identified CTC1 in a screen for telomere uncapping phenotypes, and the human CST complex was recently shown to play a role at telomeres in mammalian cells highlighting a conserved role in multi-cellular organisms [8,9]. The recent studies in Coats plus, along with the case report by Keller et al., put in focus several questions of biological and clinical significance related to the function of CTC1. While molecular analyses of CTC1 are in early stages, studies indicate