Alternative titles; symbols
HGNC Approved Gene Symbol: TERT
Cytogenetic location: 5p15.33 Genomic coordinates (GRCh38) : 5:1,253,167-1,295,068 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p15.33 | {Leukemia, acute myeloid} | 601626 | Autosomal dominant; Somatic mutation | 3 |
| {Melanoma, cutaneous malignant, 9} | 615134 | Autosomal dominant | 3 | |
| Dyskeratosis congenita, autosomal dominant 2 | 613989 | Autosomal dominant; Autosomal recessive | 3 | |
| Dyskeratosis congenita, autosomal recessive 4 | 613989 | Autosomal dominant; Autosomal recessive | 3 | |
| Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 1 | 614742 | Autosomal dominant | 3 |
Human telomeres consist of many kilobases of (TTAGGG)n together with various associated proteins. Small amounts of these terminal sequences are lost from the tips of the chromosomes each S phase because of incomplete DNA replication, but de novo addition of TTAGGG repeats by the enzyme telomerase compensates for this loss. Many human cells progressively lose terminal sequence with cell division, a loss that correlates with the apparent absence of telomerase in these cells (Kipling, 1995).
Morin (1989) identified the ribonucleoprotein telomerase in HeLa cells.
Catalytic subunits of telomerase from the ciliate Euplotes aediculatus and the yeast Saccharomyces cerevisiae contain reverse transcriptase motifs. Nakamura et al. (1997) identified homologous genes from the fission yeast Schizosaccharomyces pombe and human. The human gene encodes a 1,132-amino acid polypeptide with a predicted molecular mass greater than 100 kD. Sequence comparisons placed the telomerase proteins in the reverse transcriptase family but revealed hallmarks that distinguish them from related retroviral and retrotransposon enzymes. Thus, the proposed telomerase catalytic subunits are phylogenetically conserved and represents a deep branch in the evolution of reverse transcriptases.
Meyerson et al. (1997) cloned a human gene that shares significant sequence similarity with the telomerase catalytic subunit genes of lower eukaryotes. They referred to the gene as EST2, using the designation of the gene in Saccharomyces cerevisiae. The human EST2 gene was expressed at high levels in primary tumors, cancer cell lines, and telomerase-positive tissues, but was undetectable in telomerase-negative cell lines and differentiated telomerase-negative tissues.
Independently, Kilian et al. (1997) cloned the human telomerase catalytic subunit gene, which they symbolized TCS1.
Wick et al. (1999) identified a novel TERT splice variant.
Moriarty et al. (2005) stated that the TERT protein contains an N-terminal RNA-interaction domain (RID1), followed by a linker region, a second RNA-interaction domain (RID2), a central reverse transcriptase domain, and a C-terminal domain.
Morin (1989) found that human telomerase recognized a single-stranded G-rich telomere primer and added multiple telomeric repeats to its 3-prime end by using an RNA template in vitro.
Wilkie et al. (1990) found that a case of human alpha-thalassemia was caused by a truncation of chromosome 16 that had been healed by the addition of telomeric repeats (TTAGGG)n. Using an in vitro assay, Morin (1991) showed that human telomerase correctly recognized the chromosome 16 breakpoint sequence and added the repeats indicated. They suggested that telomerase-based chromosome healing may stabilize a broken chromosome and allow its stable inheritance. The Miller-Dieker syndrome (247200) and the Wolf-Hirschhorn syndrome (194190) are other examples of terminal chromosome deletions.
Nakamura et al. (1997) found that disruption of the S. pombe telomerase gene resulted in telomere shortening and senescence, and expression of mRNA from the human gene correlated with telomerase activity in cell lines.
Meyerson et al. (1997) found that the human EST2 transcript was upregulated concomitant with activation of telomerase during immortalization of cultured cells and was downregulated during in vitro cellular differentiation. These observations suggested that induction of EST2 mRNA expression is required for the telomerase activation that occurs during cellular immortalization and tumor progression.
Activation of telomerase, the enzyme that synthesizes the telomere ends of linear chromosomes, has been implicated in human cell immortalization and cancer cell pathogenesis. Enzyme activity is undetectable in most normal cells and tissues, but present in immortal cells and cancer tissues. Kolquist et al. (1998) used in situ hybridization to study TERT expression at the single-cell level in normal tissues and in various stages of tumor progression. In normal tissues, including some known to be telomerase-negative, TERT mRNA was present in specific subsets of cells thought to have long-term proliferative capacity. This included mitotically inactive breast lobular epithelium in addition to some actively regenerating cells such as the stratum basale of the skin. TERT expression appeared early during tumorigenesis in vivo, beginning with early preinvasive changes in human breast and colon tissues and increasing gradually during progression, both in the amount of TERT mRNA present within the individual cells and in the number of expressing cells within a neoplastic lesion. The physiologic expression of TERT within normal epithelial cells that retained proliferative potential and its presence at the earliest stages of tumorigenesis have implications for the regulation of telomerase expression and for the identification of cells that may be targets for malignant transformation.
Fossel (1998) reviewed the status of studies examining the relationship between telomerase activity and the aging process, as well as the implications of these studies for human health.
The ectopic expression of telomerase in normal human cells extends their replicative life span. Although telomerase expression is a hallmark of cancer, both Jiang et al. (1999) and Morales et al. (1999) found that cells with forced expression of the TERT gene retained normal growth control and displayed no changes associated with the malignant transformation, such as growth in soft agar or tumor formation in vivo.
The MYC protooncogene (190080) encodes a ubiquitous transcription factor involved in the control of cell proliferation and differentiation. Deregulated expression of MYC caused by gene amplification, retroviral insertion, or chromosomal translocation is associated with tumorigenesis. Understanding of the function of MYC and its role in tumorigenesis was aided by the demonstration by Wu et al. (1999) that MYC has a direct role in induction of the activity of telomerase, the ribonucleoprotein complex expressed in proliferating and transformed cells, in which it preserves chromosome integrity by maintaining telomere length. They found that MYC activates telomerase by inducing expression of its catalytic subunit, telomerase-reverse transcriptase (TERT). TERT and MYC are expressed in normal and transformed proliferating cells, and are downregulated in quiescent and terminally differentiated cells; both can induce immortalization when constitutively expressed in transfected cells. Consistent with the reported association between MYC overexpression and induction of telomerase activity (Wang et al., 1998), Wu et al. (1999) found that the TERT promoter contains numerous MYC binding sites that mediate TERT transcriptional activation. MYC-induced TERT expression is rapid and independent of cell proliferation and additional protein synthesis, consistent with direct transcriptional activation of TERT. The results indicated that TERT is a target of MYC activity and identified a pathway linking cell proliferation and chromosome integrity in normal and neoplastic cells.
Hahn et al. (1999) found that ectopic expression of TERT in combination with 2 oncogenes, the simian virus 40 (SV40) large-T oncoprotein and an oncogenic allele of HRAS (190020), resulted in direct tumorigenic conversion of normal human epithelial and fibroblast cells. When cells expressing large-T, HRAS, and TERT were introduced into nude mice, rapidly growing tumors were repeatedly observed with high efficiency. Cells carrying only large-T, large-T and HRAS, or large-T and TERT were unable to form tumors in nude mice. The authors suggested that these results demonstrated that disruption of the intracellular pathways regulated by large-T, oncogenic ras, and telomerase suffices to create a human tumor cell. Although expression of telomerase does not by itself lead to a tumorigenic phenotype, telomere maintenance facilitated by TERT expression in vivo might cooperate with additional oncogenic mutations to create a malignantly transformed clone.
Wang et al. (2000) demonstrated that TERT-driven cell proliferation is not genoprotective because it is associated with activation of the MYC oncogene. Human mammary epithelial cells, which normally stop dividing in culture at 55 to 60 population doublings (PDs), were infected with human TERT retrovirus at PD40 and maintained until PD250. Wang et al. (2000) then tested whether telomerase activity was essential for the immortalized phenotype by excising the TERT retrovirus at PD150 using Cre recombinase. The resulting cells were maintained for at least another 20 population doublings, and no decline in growth rates in either pooled cells or individual clones was observed. Ectopic expression of MYC was found to be upregulated between 107 and 135 population doublings. Wang et al. (2000) suggested that under standard culture conditions, extension of life span by telomerase selects for MYC overexpression in human mammary epithelial cells.
Shay et al. (2001) reviewed the role of telomere shortening in cell senescence, protein interactions with telomerase and telomeres, the use of telomerase in cancer diagnostics, and anti-telomerase cancer therapeutic approaches.
Cardiac muscle regeneration after injury is limited by 'irreversible' cell cycle exit. Telomere shortening is one postulated basis for replicative senescence, via downregulation of telomerase reverse transcriptase (TERT); telomere dysfunction also is associated with greater sensitivity to apoptosis. Oh et al. (2001) found that forced expression of TERT in cardiac muscle in transgenic mice was sufficient to rescue telomerase activity and telomere length. Initially, the ventricle was hypercellular, with increased myocyte density and DNA synthesis. By 12 weeks, cell cycling subsided; instead, cell enlargement (hypertrophy) was seen, without fibrosis or impaired function. Likewise, viral delivery of TERT was sufficient for hypertrophy in cultured cardiac myocytes. The TERT virus and transgene also conferred protection from apoptosis, in vitro and in vivo. Hyperplasia, hypertrophy, and survival all required active TERT and were not seen with a catalytically inactive mutation. Thus, TERT can delay cell cycle exit in cardiac muscle, induce hypertrophy in postmitotic cells, and promote cardiac myocyte survival.
Increased expression of survivin (603352) was shown to be a negative predictor of survival in patients with soft tissue sarcoma. In a study of 89 adults with soft tissue sarcomas, Wurl et al. (2002) determined that coexpression of survivin and TERT transcripts identifies patients at high risk of tumor-related death.
Resting human lymphocytes do not have telomerase activity, but activation by a variety of stimuli induces TERT expression and telomerase activity. Yago et al. (2002) found that activated human T and B lymphocytes expressed USF1 (191523) and the full-length isoform of USF2 (600390), and that dimers of these proteins bound E boxes in the TERT promoter and activated TERT expression. In contrast, resting human T and B lymphocytes expressed both the N-terminally truncated isoform of USF2 and full-length USF2, and the truncated isoform had a dominant-negative effect on TERT expression induced by full-length USF2.
Masutomi et al. (2003) demonstrated that the rate-limiting telomerase catalytic subunit TERT is expressed in cycling primary presenescent human fibroblasts, which were previously thought to lack TERT expression and telomerase activity. Disruption of telomerase activity in normal human cells slowed cell proliferation, restricted cell life span, and altered the maintenance of the 3 single-stranded telomeric overhang without changing the rate of overall telomere shortening. These observations supported the view that telomerase and telomere structure are dynamically regulated in normal human cells and that telomere length alone is unlikely to trigger entry into replicative senescence.
To explore telomerase regulation, Lin and Elledge (2003) employed a general genetic screen in HeLa cells to identify negative regulators of TERT. They discovered 3 tumor suppressor/oncogene pathways involved in TERT repression. One, the MAD1 (602686)/MYC pathway, had been previously implicated in TERT regulation. The second, SIP1 (ZEB2; 605802), a transcriptional target of the TGF-beta (190180) pathway, mediates TGF-beta-regulated repression of TERT. The third, the tumor suppressor menin (613733), is a direct repressor of TERT. Depleting menin immortalized primary human fibroblasts and caused a transformation phenotype when coupled with expression of SV40 large and small T antigen and oncogenic RAS.
To investigate whether the expression of telomerase subunits is reflected in the malignant transition of pheochromocytomas, Boltze et al. (2003) determined mRNA and/or protein expression in 28 benign and 9 malignant pheochromocytomas and compared the results with telomerase activity. RT-PCR analysis revealed that TEP1 (601686) was ubiquitously expressed. Telomerase RNA component (TERC; 602322) was found in all malignant (100%) and in 13 of 28 (46%) benign pheochromocytomas. In contrast, TERT was clearly associated with aggressive biologic behavior. All of the malignant (100%) but only 2 of 28 benign (7%) pheochromocytomas expressed TERT. HSP90 (140571) was increased in malignant pheochromocytomas, but was also expressed at a lower level in benign tumors. The authors concluded that TERT, HSP90, and telomerase activity are upregulated in malignant cells of the adrenal medulla. The common expression of TERT and telomerase activity thus represents an additional prognostic marker that may identify more aggressive tumors.
By mutation analysis, Moriarty et al. (2005) determined that the RID1 and C-terminal domains of TERT contribute to the affinity of telomerase for its substrate, and that RID1 may form part of the telomerase anchor site.
Wang et al. (2005) found that transfection of human TERT into bovine lens epithelial cells (BLECs) provided the cells with telomerase activity and significantly extended their population doublings in culture in a healthy but undifferentiated state. In contrast, control BLECs underwent terminal differentiation after comparatively few population doublings. Wang et al. (2005) demonstrated that TERT prevented replicative senescence in BLECs by synthesizing new telomeres, and that it inhibited BLEC differentiation by suppressing MEK (see 176872)/ERK (see 601795) signaling
Massard et al. (2006) found that short-term knockdown of TERT by small interfering RNA (siRNA) had no adverse effect on the viability or proliferation of HeLa and human colon carcinoma cell lines. However, TERT depletion facilitated induction of apoptotic cell death by chemotherapeutic agents, mitomycin C, and reactive oxygen species, but not by the CD95 death receptor (TNFRSF6; 134637). BAX (600040), but not p53 (TP53; 191170), was involved in the chemosensitizing effect of TERT depletion. Depletion of TERT facilitated the conformational activation of BAX induced by genotoxic agents, and BAX knockout abolished the chemosensitizing effect of TERT siRNAs. Inhibition of mitochondrial membrane permeabilization, which inhibited BAX, prevented induction of cell death by the combination of TERT depletion and chemotherapeutic agents. Massard et al. (2006) concluded that TERT inhibition facilitates apoptosis induced through the mitochondrial pathway.
Cohen et al. (2007) purified human telomerase 10(8)-fold, with the final elution dependent on the enzyme's ability to catalyze nucleotide addition onto a DNA oligonucleotide of telomeric sequence, thereby providing specificity for catalytically active telomerase. Mass spectrometric sequencing of the protein components and molecular size determination indicated an enzyme composition of 2 molecules each of TERT, TERC, and dyskerin (DKC1; 300126).
Tomas-Loba et al. (2008) engineered mice to be cancer resistant via enhanced expression of several tumor suppressors. Tert overexpression in these mice improved the fitness of epithelial barriers, particularly skin and intestine, and produced a systemic delay in aging accompanied by extension of the median life span.
Venteicher et al. (2009) showed that TCAB1 (612661) associates with TERT, established telomerase components dyskerin and TERC, and small Cajal body RNAs (scaRNAs), which are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevented TERC from associating with Cajal bodies, disrupted telomerase-telomere association, and abrogated telomere synthesis in telomerase. Thus, Venteicher et al. (2009) concluded that TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells.
Park et al. (2009) demonstrated that telomerase directly modulates Wnt/beta-catenin (see 116806) signaling by serving as a cofactor in a beta-catenin transcriptional complex. The telomerase protein component TERT interacts with BRG1 (SMARCA4; 603254), a SWI/SNF-related chromatin remodeling protein, and activates Wnt-dependent reporters in cultured cells and in vivo. TERT serves an essential role in formation of the anterior-posterior axis in Xenopus laevis embryos, and this defect in Wnt signaling manifests as homeotic transformations in the vertebrae of Tert-null mice. Chromatin immunoprecipitation of the endogenous TERT protein from mouse gastrointestinal tract showed that TERT physically occupies gene promoters of Wnt-dependent genes such as AXIN2 (604025) and MYC (190080). Park et al. (2009) concluded that their data revealed an unanticipated role for telomerase as a transcriptional modulator of the Wnt/beta-catenin signaling pathway.
Maida et al. (2009) demonstrated that TERT interacts with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP; 157660), the gene that is mutated in cartilage-hair hypoplasia (250250). Human TERT and RMRP form a distinct ribonucleoprotein complex that has RNA-dependent RNA polymerase activity and produces double-stranded RNAs that can be processed into small interfering RNA (siRNA) in a Dicer (606241)-dependent manner. The human TERT-RMRP RNA-dependent RNA polymerase (RdRP) shows a strong preference for RNA templates that can form 3-prime fold-back structures. Using RMRP as a template, the TERT-RMRP RdRP produces double-stranded RNAs that are processed by Dicer into 22-nucleotide double-stranded RNAs that contain 5-prime monophosphate and 3-prime hydroxyl groups that are loaded into AGO2 (606229), confirming that these short RNAs represent endogenous siRNAs. The involvement of human TERT in 2 syndromes characterized by stem cell failure (cartilage-hair hypoplasia and dyskeratosis congenita, 127550) suggested to Maida et al. (2009) that ribonucleoprotein complexes containing TERT have a critical role in stem cell biology.
A cardinal feature of induced pluripotent stem cells (iPS) is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene TERT. Agarwal et al. (2010) investigated whether defects in telomerase function would limit derivation maintenance of iPS cells from patients with dyskeratosis congenita (DKC). The authors showed that reprogrammed DKC cells overcome a critical limitation in telomerase RNA component (TERC; 602322) levels to restore telomere maintenance and self-renewal. Agarwal et al. (2010) discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DKC, transcriptional silencing accompanies a 3-prime deletion at the TERC locus. Agarwal et al. (2010) concluded that their results demonstrated that reprogramming restores telomere elongation in DKC cells despite genetic lesions affecting telomerase, and showed that strategies to increase TERC expression may be therapeutically beneficial in DKC.
Hoffmeyer et al. (2012) reported a molecular link between Wnt/beta-catenin signaling and the expression of the telomerase subunit Tert. Beta-catenin-deficient mouse embryonic stem cells have short telomeres; conversely, embryonic stem cells expressing an activated form of beta-catenin (beta-catenin(deltaEx3/+)) have long telomeres. Hoffmeyer et al. (2012) showed that beta-catenin regulates Tert expression through the interaction with Klf4 (602253), a core component of the pluripotency transcriptional network. Beta-catenin binds to the Tert promoter in a mouse intestinal tumor model and in human carcinoma cells. Hoffmeyer et al. (2012) uncovered a theretofore unknown link between the stem cell and oncogenic potential whereby beta-catenin regulates Tert expression, and thereby telomere length, which could be critical in human regenerative therapy and cancer.
Reactivation of TERT expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (137800), harbor highly recurrent TERT promoter mutations of unknown function but specific to 2 nucleotide positions. Bell et al. (2015) identified the functional consequence of these mutations in glioblastomas to be recruitment of the multimeric GA-binding protein transcription factor (GABP; see 600609) specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across 4 cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. Bell et al. (2015) concluded that GABP directly links TERT promoter mutations to aberrant expression in multiple cancers.
Peifer et al. (2015) performed whole-genome sequencing of 56 neuroblastomas (39 high-risk and 17 low-risk) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal to TERT. These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN (164840) amplifications and ATRX (300032) mutations, which are known genetic events in this tumor type. In an extended case series of 217 neuroblastomas, TERT rearrangements defined a subgroup of high-risk tumors with particularly poor outcome. Despite the high structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumors, TERT expression was also elevated in MYCN-amplified tumors, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodeling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. Peifer et al. (2015) concluded that their findings showed that remodeling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the center of transformation in a large fraction of these tumors.
Lin et al. (2018) identified a subset of hepatocytes that expresses high levels of telomerase and showed that this hepatocyte subset repopulates the liver during homeostasis and injury. Using lineage tracing from the Tert locus in mice, Lin et al. (2018) demonstrated that rare hepatocytes with high telomerase expression are distributed throughout the liver lobule. During homeostasis, these cells regenerate hepatocytes in all lobular zones, and both self-renew and differentiate to yield expanding hepatocyte clones that eventually dominate the liver. In response to injury, the repopulating activity of TERT(High) hepatocytes is accelerated, and their progeny cross zonal boundaries. RNA sequencing showed that metabolic genes are downregulated in TERT(High) hepatocytes, indicating that metabolic activity and repopulating activity may be segregated within the hepatocyte lineage. Genetic ablation of TERT(High) hepatocytes combined with chemical injury caused a marked increase in stellate cell activation and fibrosis. Lin et al. (2018) concluded that their results provided support for a distributed model of hepatocyte renewal in which a subset of hepatocytes dispersed throughout the lobule clonally expands to maintain liver mass.
To investigate mechanisms of TERT gene expression, Cong et al. (1999) cloned genomic sequences which encompassed the complete TERT transcription unit. They found that the gene consists of 16 exons and 15 introns spanning approximately 35 kb. Transient transfections of immortal human cells with potential regulatory 5-prime sequences linked to a reporter, combined with deletion analysis of these sequences, indicated that elements responsible for promoter activity are contained within a region extending from 330 bp upstream of the ATG to the second exon of the gene. Assays in different cell types showed that the human TERT promoter is inactive in normal and in transformed pre-immortal cells, but, like telomerase, it is activated with cell immortalization. Sequence analysis showed that the TERT promoter is GC-rich, lacks TATA and CAAT boxes, but contains binding sites for several transcription factors that may be involved in its regulation. The abundance of these sites suggested that TERT expression may be subject to multiple levels of control and may be regulated by different factors in different cellular contexts.
Wick et al. (1999) characterized the genomic organization and promoter of the TERT gene. It encompasses more than 37 kb and contains 16 exons. They showed that all insertion and deletion variants described to that time most likely resulted from the use of alternative splice consensus sequences in intron or exon regions.
Renaud et al. (2003) found that the TERT core promoter region just upstream of the translation initiation site had bidirectional activity, a common feature of TATA-less promoters. They identified a splicing regulatory region upstream of the core promoter and 2 regions, one upstream of the core promoter and the other within the 5-prime end of the coding region, that negatively regulated TERT promoter activity.
By study of radiation hybrid analysis, Meyerson et al. (1997) mapped the TERT gene to chromosome 5p15.33, close to marker D5S678.
Townsley et al. (2016) performed a phase 1-2 prospective study involving patients with telomere diseases by administering the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. Of 21 of 27 patients in whom a mutation had been identified, 10 patients carried a mutation in TERT. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy endpoint was a 20% reduction in the annual rate of telomere attrition measured at 24 months. After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary endpoint; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval (CI) 26 to 64) met the primary efficacy endpoint. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months compared with baseline (mean increase, 386 bp, 95% CI 178 to 593); exploratory analyses showed results at 6 months and 12 months. Hematologic responses occurred in 19 of 24 patients who could be evaluated at 3 months. Known adverse effects of danazol (elevated liver enzymes and muscle cramps) of grade 2 or less occurred in 41% and 33% of the patients, respectively.
Dyskeratosis Congenita, Autosomal Dominant 2
In all 6 affected members of a family with autosomal dominant dyskeratosis congenita-2 (DKCA2; 613989), Armanios et al. (2005) identified a heterozygous mutation in the TERT gene (187270.0007). Anticipation of clinical features was observed, and all affected individuals showed increased frequency of short telomeres compared to unaffected family members.
Basel-Vanagaite et al. (2008) identified a heterozygous mutation in the TERT gene (R631Q; 187270.0011) in affected members of an Iraqi Jewish family with autosomal dominant dyskeratosis congenita-2.
Dyskeratosis Congenita, Autosomal Recessive 4
Marrone et al. (2007) identified homozygous TERT mutations (R901W, 187270.0012 and P704S, 187270.0013) in patients with a severe form of autosomal recessive dyskeratosis congenita-4 (DKCB4; see 613989).
In a Turkish child, born to consanguineous parents, with DKCB4, Cepni et al. (2022) identified a homozygous missense mutation (R671W; 187270.0024) in the TERT gene. The mutation, which was found by trio whole-exome sequencing, was present in heterozygous state in both parents and multiple other maternal and paternal family members. The patient had very short telomeres in lymphocytes and granulocytes, consistent with an infantile telomere biology disorder. The patient's father, mother, and carrier maternal grandfather had short telomeres in lymphocytes and granulocytes, and all 3 had premature graying of the hair.
Telomere-Related Pulmonary Fibrosis and/or Bone Marrow Failure Syndrome 1
Mutations in the TERC gene cause short telomeres in autosomal dominant congenital aplastic anemia of dyskeratosis congenita-1 (DKCA1; 127550) and in some cases of apparently acquired aplastic anemia. Yamaguchi et al. (2005) investigated whether mutations in genes for other components of telomerase also occur in patients with aplastic anemia due to bone marrow failure (PFBMFT1; 614742). They found 5 heterozygous, nonsynonymous mutations in TERT (187270.0001-187270.0005) among 7 unrelated patients. Leukocytes from these patients had short telomeres and low telomerase enzymatic activity. Three patients had a relative with myelodysplastic syndrome, one of whom had acute myeloid leukemia. In 1 family, 4 individuals with the mutation also had short telomeres and reduced telomerase activity, but no evident hematologic abnormality. The results of coexpression of wildtype TERT and TERT with aplastic anemia-associated mutations in a telomerase-deficient cell line suggested that haploinsufficiency was the mechanism of telomere shortening due to TERT mutations.
Tsakiri et al. (2007) performed a genomewide linkage scan in 2 large Caucasian families with interstitial lung disease, many cases of which met the clinical criteria for idiopathic pulmonary fibrosis, and found linkage to chromosome 5p15 with a maximum lod score of 2.8. Sequencing TERT, a candidate gene in the interval, revealed heterozygosity for a missense mutation (187270.0008) and a frameshift mutation (187270.0009) that cosegregated with pulmonary disease in the 2 families, respectively. Analysis of the TERT gene in probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed 5 other heterozygous mutations. Although all family members with pulmonary fibrosis were heterozygous for these mutations, some carriers had no evidence of pulmonary disease; however, heterozygous carriers of TERT mutations had some clinical features of DKC, including anemia, osteoporosis or osteopenia, cirrhosis, and cancer. Mutation carriers had shorter telomeres than age-matched family members without the mutations. Tsakiri et al. (2007) concluded that mutations in TERT that result in telomere shortening over time confer a dramatic increase in susceptibility to adult-onset pulmonary fibrosis.
Armanios et al. (2007) screened 73 probands with familial idiopathic pulmonary fibrosis for mutations in the TERT or TERC genes and identified 5 mutations in TERT (see, e.g., 187270.0010) and 1 in TERC (602322.0009) in 6 probands, respectively. Average telomere length was significantly less in probands and asymptomatic mutation carriers than in relatives who did not carry the mutation (p = 0.006), suggesting that asymptomatic carriers may also be at risk for the disease. None of the classic features of dyskeratosis congenita were seen in the 5 families carrying a mutation in the TERT gene.
In affected members of 2 unrelated families with variable manifestations of telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-1, Kirwan et al. (2009) identified 2 different heterozygous mutations in the TERT gene. One mutation carrier presented with myelodysplastic syndrome (MDS) and another with MDS/acute myeloid leukemia (AML). Each family contained at least 1 asymptomatic member who carried the mutation, suggesting incomplete penetrance and that the mutations are risk factors for development of the disease. Mutation carriers had short telomeres, and there was a correlation between shorter telomere length and disease manifestation. Overall, Kirwan et al. (2009) identified TERT or TERC mutations in 4 of 20 families presenting with MDS/AML.
Susceptibility to Cutaneous Malignant Melanoma
Horn et al. (2013) reported a 4-generation family with malignant melanoma segregating a T-to-G transversion at the -57 position from the ATG translation start site of TERT (187270.0023). The mutation was found in all 4 affected family members sequenced and in 1 of 4 unaffected family members. Two family members had additional forms of cancer. This mutation was not found among 140 sporadic melanoma cases, 165 healthy controls, index cases from 34 Spanish melanoma families, or in the dbSNP or 1000 Genomes Project databases. Horn et al. (2013) screened 168 melanoma cell lines derived from sporadic cases of metastatic melanoma, none of which carried the germline mutation found in the melanoma-prone family studied by them. They identified recurrent ultraviolet signature mutations in the TERT core promoter in 125 cell lines (74%), in 45 of 53 corresponding metastatic tumor tissues (85%) and in 25 of 77 (33%) primary melanomas. Two frequent mutations, G-to-A (C-to-T on the opposite strand) transitions at positions -124 and -146, were mutually exclusive and occurred in 27% and 38% of cell lines, respectively. These mutations generate binding motifs for Ets/TCF (ternary complex factor) transcription factors. Among 77 paraffin-embedded primary melanoma tumors, the -124G-A mutation was found in 7 (9%) and the -146G-A mutation in 5 (7%).
Huang et al. (2013) independently found the -124G-A and -146G-A TERT promoter mutations, which they called C228T and C250T, respectively, in 50 of 70 (71%) of melanomas examined. These mutations generate de novo consensus binding motifs for ETS transcription factors and increased transcriptional activity from the TERT promoter by 2- to 4-fold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same 2 mutations in 24 cases (16%) with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. The C228T/-124G-A mutation occurs at genomic coordinate chr5:1,295,228 (GRCh37), and C250T/-146G-A at chr5:1,295,250 (GRCh37).
Chiba et al. (2017) demonstrated that TERT promoter mutations acquired at the transition from benign nevus to malignant melanoma do not support telomere maintenance. In vitro experiments revealed that TERT promoter mutations do not prevent telomere attrition, resulting in cells with critically short and unprotected telomeres. Immortalization by TERT promoter mutations requires a gradual upregulation of telomerase, coinciding with telomere fusions. These data suggested that TERT promoter mutations contribute to tumorigenesis by promoting immortalization and genomic instability in 2 phases. In an initial phase, TERT promoter mutations do not prevent bulk telomere shortening but extend cellular life span by healing the shortest telomeres. In the second phase, the critically short telomeres lead to genome instability and telomerase is further upregulated to sustain cell proliferation.
Other Disease Associations
Zhang et al. (2003) demonstrated that heterozygous deletion of TERT occurred in all 10 patients with cri-du-chat syndrome (123450) whom they examined. Induction of TERT mRNA in proliferating lymphocytes derived from 5 of 7 patients was lower than that in unaffected control individuals. Patient lymphocytes exhibited shorter telomeres than age-matched unaffected controls (p less than 0.0001). A reduction in replicative life span and a high rate of chromosome fusions were observed in cultured patient fibroblasts. Reconstitution of telomerase activity by ectopic expression of TERT extended the telomere length, increased the population doublings, and prevented the end-to-end fusion of chromosomes.
Calado et al. (2009) found a significantly increased number of germline mutations in the TERT gene in patients with sporadic acute myeloid leukemia (AML; 601626) compared to controls. One mutation in particular, A1062T (187270.0022), was 3-fold higher among 594 AML patients compared to 1,110 controls (p = 0.0009). In vitro studies showed that the mutations caused haploinsufficiency of telomerase activity. An abnormal karyotype was found in 18 of 21 patients with TERT mutations who were tested. Calado et al. (2009) suggested that telomere attrition may promote genomic instability and DNA damage, which may contribute to the development of leukemia.
For discussion of a possible association between a -1327T-C polymorphism in the promoter region of the TERT gene and coronary artery disease and telomere length in Japanese patients, see (187270.0006).
For discussion of a possible association between variation in the TERT gene and lung cancer, see 612571.
For discussion of a possible association between variation in the TERT gene and glioma, see GLM8 (613033).
For discussion of a possible association between variation in the TERT gene and cancer risk in Lynch syndrome, see 120435.
Borah et al. (2015) studied 23 human urothelial cancer (see 109800) cell lines and showed that point mutations in the TERT promoter correlate with higher levels of TERT mRNA, TERT protein, telomerase enzymatic activity, and telomere length. Although previous studies found no relation between TERT promoter mutations and urothelial cancer patient outcome, Borah et al. (2015) found that elevated TERT mRNA expression strongly correlates with reduced disease-specific survival in 2 independent urothelial cancer patient cohorts (n = 35; n = 87). Borah et al. (2015) concluded that their results suggested that high telomerase activity may be a better marker of aggressive urothelial cancer tumors than TERT promoter mutations alone.
Gonzalez-Suarez et al. (2002) developed transgenic mice with overexpression of Tert targeted to basal keratinocytes of stratified epithelia. They had previously found that, upon exposure to chemical carcinogens, transgenic epithelia showed a higher susceptibility to developing papillomas. Transgenics also showed a faster rate of wound healing and a higher proliferation rate upon mitogenic stimuli than wildtype animals. In order to determine the impact of telomerase overexpression with aging, Gonzalez-Suarez et al. (2002) maintained several transgenic founder lines for more than 2 years. In comparison to wildtype controls, transgenics showed a decreased life span that was associated with a higher incidence of preneoplastic and neoplastic lesions in various tissues. Neoplasia was coincident with Tert overexpression in affected tissues. The increased cancer incidence and reduced viability was aggravated when the transgene was introduced into a p53 +/- background.
Sarin et al. (2005) showed that conditional transgenic induction of Tert in mouse skin epithelium causes a rapid transition from telogen (the resting phase of the hair follicle cycle) to anagen (the active phase), thereby facilitating robust hair growth. Tert overexpression promotes this developmental transition by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. Sarin et al. (2005) demonstrated that this function for TERT does not require TERC, which encodes the template for telomere addition, and therefore operates through a mechanism independent of its activity in synthesizing telomere repeats. Sarin et al. (2005) concluded that their data indicate that, in addition to its established roles in extending telomeres, TERT can promote proliferation of resting stem cells through a noncanonical pathway.
Flores et al. (2005) showed through analysis of mouse models that telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of epidermal stem cells. Telomere shortening inhibited mobilization of stem cells out of their niche, impaired hair growth, and resulted in suppression of stem cell proliferative capacity in vitro. In contrast, Tert overexpression in the absence of changes in telomere length promoted stem cell mobilization, hair growth, and stem cell proliferation in vitro. Flores et al. (2005) concluded that the effects of telomeres and telomerase on stem cell biology anticipate their role in cancer and aging.
Expression of TERT in human tissues is significantly different from that in mouse tissues. Using transgenic mice expressing human TERT and mutation analysis, Horikawa et al. (2005) determined that a nonconserved GC box within the human TERT promoter is responsible for repression of TERT expression in certain tissues, such as liver, kidney, lung, uterus, and fibroblasts. They concluded that a difference in cis regulation of transcription, rather than transacting transcription factors, is critical to species differences in tissue-specific TERT expression.
Armanios et al. (2009) generated wildtype mice with short telomeres. In these mice, Armanios et al. (2009) identified hematopoietic and immune defects that resembled those present in patients with dyskeratosis congenita (see 305000). Patients with dyskeratosis congenita have a premature aging syndrome that can be caused by mutations in the RNA or catalytic component of telomerase. When mice with short telomeres were interbred, telomere length was only incrementally restored, and even several generations later, wildtype mice with short telomeres still displayed degenerative defects. Armanios et al. (2009) concluded that their findings implicated telomere length as a unique heritable trait and demonstrated that short telomeres are sufficient to mediate the degenerative defects of aging.
Jaskelioff et al. (2011) sought to determine whether entrenched multisystem degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, they engineered a knockin allele encoding a 4-hydroxytamoxifen-inducible telomerase reverse transcriptase-estrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice had short dysfunctional telomeres and sustained increased DNA damage signaling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extended telomeres, reduced DNA damage signaling and associated cellular checkpoint responses, allowed resumption of proliferation in quiescent cultures, and eliminated degenerative phenotypes across multiple organs including testes, spleen, and intestine. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2 (184429)+ neural progenitors, Dcx (300121)+ newborn neurons, and Olig2 (606386)+ oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Jaskelioff et al. (2011) concluded that accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk, and the marked reversal of systemic degenerative phenotypes in adult mice observed by them, supported the development of regenerative strategies designed to restore telomere integrity.
In 2 unrelated patients with telomere-related bone marrow failure (PFBMFT1; 614742), Yamaguchi et al. (2005) identified heterozygosity for an ala202-to-thr missense mutation (A202T) in exon 2 of the TERT gene. Study of 1 patient's family suggested that short telomeres were associated with the presence of the same mutation in 3 of 4 sibs of the proband and in 1 of 2 daughters of the proband. No abnormalities in peripheral blood cell counts were present in these carriers; only the proband was pancytopenic. Telomere length in patient granulocytes was less than 10% of control values, and cell lysates carrying the mutation showed less than 1% telomerase activity.
In 2 unrelated patients with telomere-related bone marrow failure (PFBMFT1; 614742), Yamaguchi et al. (2005) identified heterozygosity for a his412-to-tyr missense mutation (H412Y) in exon 2 of the TERT gene. Telomere length in patient granulocytes was less than 10% of control values, and cell lysates carrying the mutation showed about 50% telomerase activity.
In a Scottish man with autosomal recessive dyskeratosis congenita-4 (DKCB4; see 613989), Du et al. (2008) identified compound heterozygosity for H412Y and P704S (187270.0014). Du et al. (2008) showed that the mutant H412Y protein had 36% residual activity.
In a patient with telomere-related bone marrow failure (PFBMFT1; 614742), Yamaguchi et al. (2005) identified heterozygosity for a val694-to-met missense mutation (V694M) in exon 5 of the TERT gene. Telomere length in patient granulocytes was less than 10% of control values, and cell lysates carrying the mutation showed less than 1% telomerase activity.
In a patient with telomere-related bone marrow failure (PFBMFT1; 614742), Yamaguchi et al. (2005) identified heterozygosity for a tyr772-to-cys missense mutation (Y772C) in exon 7 of the TERT gene. Telomere length in patient granulocytes was less than 1% of control values, and cell lysates carrying the mutation showed less than 1% telomerase activity.
In a patient with severe telomere-related bone marrow failure (PFBMFT1; 614742), Yamaguchi et al. (2005) identified heterozygosity for a val1090-to-met missense mutation (V1090M) in exon 15 of the TERT gene. Telomere length in patient granulocytes was less than 1% of control values, and cell lysates carrying the mutation showed less than 1% telomerase activity.
This variant, formerly titled CORONARY ARTERY DISEASE, SUSCEPTIBILITY TO, has been reclassified because its contribution to the disease has not been confirmed.
Matsubara et al. (2006) examined the -1327T-C promoter polymorphism in 104 Japanese male patients with coronary artery disease (CAD) and 115 age-matched male controls and found an association between the -1327 CC genotype and CAD (p = 0.0218). Among the 104 CAD patients, the CC genotype was also associated with shorter telomere length (p = 0.0287). Matsubara et al. (2006) suggested that the -1327 CC genotype is a risk factor for CAD and that it relates to shorter telomere length among CAD patients.
In all 6 affected members of a 3-generation family with autosomal dominant dyskeratosis congenita-2 (DKCA2; 613989), Armanios et al. (2005) identified heterozygosity for a G-to-C transversion in exon 11 of the TERT gene, resulting in a lys902-to-asn (K902N) substitution in a highly conserved residue. In vitro functional expression studies showed that the K902N mutant protein had almost no telomerase activity, resulting in haploinsufficiency.
In a 58-year-old man with telomere-related pulmonary fibrosis (PFBMFT1; 614742) from a 4-generation Caucasian family with interstitial lung disease, Tsakiri et al. (2007) identified a heterozygous 2594G-A transition in the TERT gene, resulting in an arg865-to-his (R865H) substitution in the consensus sequence of motif C, which is conserved in all reverse transcriptase proteins. The mutant protein had about 30% residual activity and affected individuals had shorter telomeres compared to family members without the mutation. Three mutation carriers had anemia, 4 had osteoporosis or osteopenia, 2 had cancer, and 1 had cirrhosis, but 2 mutation carriers did not have lung disease.
In a 67-year-old man with telomere-related pulmonary fibrosis (PFBMFT1; 614742) from a 4-generation Caucasian family with interstitial lung disease, Tsakiri et al. (2007) identified a heterozygous 1-bp deletion (2240delT) in the TERT gene, creating a frameshift predicted to result in a truncated protein missing half of the reverse-transcriptase domain and the entire C terminus (Val747fsTer766). The mutant protein had essentially no enzymatic activity. There were 5 members of the next generation who inherited the mutation but had no evidence of pulmonary disease, but all carriers of the mutation had shorter telomeres than age-matched family members without the mutation. One mutation carrier had anemia, 2 had osteopenia or osteoporosis, and 1 had lymphoma.
In a male nonsmoker with telomere-related pulmonary fibrosis (PFBMFT1; 614742) who was diagnosed at 58 years of age and died at age 67 years, Armanios et al. (2007) identified heterozygosity for a +1G-A transition in intron 1 of the TERT gene, located at a consensus sequence conserved in 99.9% of all eukaryotic genes and predicted to alter splicing. The mutation was also found in his 2 affected sibs and in his as yet unaffected daughter and niece; the mutation was not found in 623 controls. Telomere length in the lymphocytes of the unaffected niece was less than 1% of controls. None of the mutation carriers had skin manifestations or evidence of bone marrow involvement.
In affected members of an Iraqi Jewish family with autosomal dominant dyskeratosis congenita-2 (DKCA2; 613989), Basel-Vanagaite et al. (2008) identified a heterozygous 1892G-A transition in the TERT gene, resulting in an arg631-to-gln (R631Q) substitution in a conserved residue in motif 2 of the RT domain. Affected males presented with thrombocytopenia, and later developed aplastic anemia, premature graying of the hair, and pulmonary and hepatic fibrosis. One patient developed cardiac fibrosis and another developed dilated cardiomyopathy. Anticipation for these features was observed. While all 6 males of the family were severely affected, 2 female mutation carriers had only premature gray hair; however, all mutation carriers had a similar shortening of telomere length.
In a 13-year-old Libyan girl, born of consanguineous parents, with autosomal recessive dyskeratosis congenita-4 (DKCB4; see 613989), Marrone et al. (2007) identified a homozygous 2431C-T transition in exon 8 of the TERT gene, resulting in an arg811-to-cys (R811C) substitution in the nonconserved region of the RT domain. In vitro functional expression assays showed that the mutant protein had less than 50% residual activity, and there was no evidence of a dominant-negative effect. The patient had poor growth, bone marrow failure, reticulated pigmentation of the skin, leukoplakia, and nail dysplasia. Her parents, who were each heterozygous for the mutation, had mild manifestations, such as dysplastic toenails and hyperpigmented skin.
In a 3-year-old girl, born of consanguineous Iranian-Jewish parents, with autosomal recessive dyskeratosis congenita-4 (DKCB4; see 613989), Marrone et al. (2007) identified a homozygous 2701C-T transition in exon 11 of the TERT gene, resulting in an arg901-to-trp (R901W) substitution in a conserved D motif of the RT domain. In vitro functional expression assays showed that the mutant protein had less than 25% residual activity, and there was no evidence of a dominant-negative effect. The parents were heterozygous for the mutation, confirming autosomal recessive inheritance. The patient had early bone marrow failure, leukoplakia, failure to thrive, cerebellar hypoplasia, microcephaly, and developmental delay. Telomere lengths were severely shortened in the patient and at the low-normal level in both parents. Marrone et al. (2007) noted that the presence of developmental delay and cerebellar hypoplasia was consistent with a clinical diagnosis of Hoyeraal-Hreidarsson syndrome, which is a severe variant of DKC.
In a 31-year-old Scottish man with autosomal recessive dyskeratosis congenita-4 (DKCB4; see 613989), Du et al. (2008) identified a homozygous 2110C-T transition in exon 5 of the TERT gene, resulting in a pro704-to-ser (P704S) substitution. Functional analysis showed that the mutant protein had 13% residual activity. The patient had short stature, elfin appearance, esophageal stricture, leukoplakia of the buccal mucosa, anus, and penis, abnormal pigmentation, hyperkeratosis of his palms, ridged fingernails, avascular necrosis of both hips, tooth loss, chronic diarrhea, learning difficulties, pulmonary infiltrates, and progressive bone marrow failure. The mother, who healthy, was heterozygous for the P704S mutation. The father, who had osteoporosis at age 61, was compound heterozygous for P704S and another mutation (H412Y; 187270.0002). However, he had normal peripheral blood counts. Coexpression of the 2 TERT mutations in the father resulted in an intermediate telomerase activity of 22%. Both the proband and his father had very short telomeres.
In a man with onset of telomere-related pulmonary fibrosis (PFBMFT1; 614742) at age 77 years, Armanios et al. (2007) identified a heterozygous T-to-A transversion in the TERT gene, resulting in a leu55-to-gln (L55Q) substitution. A brother had died of the disease, but no DNA was available for study. Two of the proband's asymptomatic children also carried the mutation. Telomere length in 2 mutation carriers was less than 10% of control values. None of the mutation carriers had skin manifestations or evidence of bone marrow involvement.
In a woman with onset of telomere-related pulmonary fibrosis (PFBMFT1; 614742) at age 48 years, Armanios et al. (2007) identified a heterozygous A-to-C transversion in intron 9 of the TERT gene (IVS9-2A-C). Her unaffected brother also carried the mutation; telomere length in his lymphocytes was less than 10% of control values. The proband did not have skin manifestations or evidence of bone marrow involvement.
In affected members of 2 unrelated families with telomere-related pulmonary fibrosis (PFBMFT1; 614742), Alder et al. (2011) identified heterozygosity for an allele carrying 2 mutations in cis in the TERT gene: a 2371G-A transition in exon 7 and a 2599G-A transition in exon 10, resulting in a val791-to-ile (V791I) and a val867-to-met (V867M) substitution, respectively. The mutations were not found in 200 controls. In 1 family, the mutant allele segregated with the phenotype across 3 generations. Haplotype analysis and family histories of the 2 families indicated a founder effect. A common ancestor had emigrated from the British Isles to the United States in the 18th century. In vitro functional expression studies showed that the double mutant showed severe defects in telomere repeat addition processivity, with the V867M mutation causing most, if not all, of the functional defects. All mutation carriers had telomere lengths below the 10th percentile, and 6 of 9 mutation carriers had lengths below the 1st percentile. Most mutation carriers had adult-onset pulmonary fibrosis, 2 had liver abnormalities, 1 had cytopenia, and 1 developed acute myeloid leukemia. None had abnormal skin findings.
In affected members of 2 unrelated families with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-1 (PFBMFT1; 614742), Parry et al. (2011) identified a heterozygous mutation in the TERT gene, resulting in a val170-to-met (V170M) substitution. One mutation carrier had liver disease. The V170M mutation was demonstrated to cause decreased telomerase activity (about 65% of control activity).
In affected members of a family with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-1 (PFBMFT1; 614742), Parry et al. (2011) identified a heterozygous mutation in the TERT gene, resulting in an ala716-to-thr (A716T) substitution. The A726T mutation was demonstrated to cause severely compromised telomerase activity (close to 0%).
In affected members of a family with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-1 (PFBMFT1; 614742), Parry et al. (2011) identified a heterozygous mutation in the TERT gene, resulting in a lys902-to-asn (K902N) substitution. Two mutation carriers had liver disease.
In a 56-year-old man with telomere-related pulmonary fibrosis and bone marrow failure syndrome-1 (PFBMFT1; 614742), Gansner et al. (2012) identified a heterozygous 2768C-T transition in the TERT gene, resulting in a pro923-to-leu (P923L) substitution in a conserved residue in the putative oligomerization domain. The patient had a family history of a similar disorder: his father and 1 sister had pulmonary fibrosis, a second sister had pulmonary fibrosis and thrombocytopenia, and a third sister had pulmonary fibrosis and acute myeloid leukemia. Telomere lengths in the proband were less than 1% of control values.
Calado et al. (2009) found a significant association between the presence of a germline ala1062-to-thr (A1062T) mutation in the TERT gene in patients with sporadic acute myeloid leukemia (AML; 601626) compared to controls. A1062T was 3-fold higher among 594 patients compared to 1,110 controls (p = 0.0009). In vitro studies showed that the mutation caused haploinsufficiency of telomerase activity. A high proportion of mutation carriers had an abnormal karyotype. Calado et al. (2009) suggested that telomere attrition may promote genomic instability and DNA damage, which may contribute to the development of leukemia.
In affected members of a 4-generation family prone to malignant melanoma (CMM9; 615134), Horn et al. (2013) identified a T-to-G transversion at the -57 position of the TERT promoter. Affected individuals developed melanoma at a young age and 2 individuals had additional forms of cancer. This mutation was not found among 140 sporadic melanoma cases, 165 healthy controls, index cases from 34 Spanish melanoma families, or in the dbSNP or 1000 Genomes Project databases.
In a Turkish child, born to consanguineous parents, with autosomal recessive dyskeratosis congenita-4 (DKCB4; see 613989), Cepni et al. (2022) identified a homozygous c.2011C-T transition (c.2011C-T, NM_198253.3) in the TERT gene, resulting in an arg671-to-trp (R671W) substitution. The mutation, which was found by trio whole-exome sequencing and confirmed by Sanger sequencing, was present in the carrier state in both parents and multiple other maternal and paternal family members. The mutation was not present in the 1000 Genomes Project, gnomAD, ExAC, and ESP databases. The patient had very short telomeres in lymphocytes and granulocytes, consistent with an infantile telomere biology disorder. The patient's parents and carrier maternal grandfather had short telomeres in lymphocytes and granulocytes, and all 3 had premature graying of the hair.
In a 16-year-old girl (patient 4) with autosomal dominant dyskeratosis congenita-2 (DKCA2; 613989), Jonassaint et al. (2013) identified a heterozygous c.3075G-T transversion in exon 14 of the TERT gene, resulting in a val1025-to-phe (V1025F) substitution. In addition to aplastic anemia requiring a bone marrow transplant, she had significant gastrointestinal disease manifest as failure to thrive, early satiety, and watery diarrhea. Upper endoscopy showed inflammatory changes in the esophagus; lower endoscopy was not performed. Her symptoms progressed after the bone marrow transplant, and she was placed on total parenteral nutrition. Other features included pulmonary fibrosis and immunodeficiency.
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