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Journal articles on the topic 'RTEL1'

Author: Grafiati

Published: 4 June 2021

Last updated: 25 May 2024

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1

Landry, Aaron P., and Huangen Ding. "The N-Terminal Domain of Human DNA Helicase Rtel1 Contains a Redox Active Iron-Sulfur Cluster." BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/285791.

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Human telomere length regulator Rtel1 is a superfamily II DNA helicase and is essential for maintaining proper length of telomeres in chromosomes. Here we report that the N-terminal domain of human Rtel1 (RtelN) expressed inEscherichia colicells produces a protein that contains a redox active iron-sulfur cluster with the redox midpoint potential of −248 ± 10 mV (pH 8.0). The iron-sulfur cluster in RtelN is sensitive to hydrogen peroxide and nitric oxide, indicating that reactive oxygen/nitrogen species may modulate the DNA helicase activity of Rtel1 via modification of its iron-sulfur cluster. Purified RtelN retains a weak binding affinity for the single-stranded (ss) and double-stranded (ds) DNAin vitro. However, modification of the iron-sulfur cluster by hydrogen peroxide or nitric oxide does not significantly affect the DNA binding activity of RtelN, suggesting that the iron-sulfur cluster is not directly involved in the DNA interaction in the N-terminal domain of Rtel1.

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Gutierrez-Rodrigues, Fernanda, Sachiko Kajigaya, Xingmin Feng, Maria del Pilar Fernandez Ibanez, Marie J. Desierto, Keyvan Keyvanfar, Zejuan Li, et al. "Heterozygous RTEL1 variants in Patients with Bone Marrow Failure Associate with Telomere Dysfunction in the Absence of Telomere Shortening." Blood 128, no. 22 (December 2, 2016): 1044. http://dx.doi.org/10.1182/blood.v128.22.1044.1044.

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Abstract The pathophysiology of bone marrow failure (BMF) can be immune, as in acquired aplastic anemia (AA), or constitutional, due to germline mutations in genes critical for DNA repair and telomere maintenance. Variability in penetrance and phenotype can complicate diagnosis, as patients with underlying genetic defects may present in adulthood and without characteristic physical anomalies. RTEL1 encodes a helicase crucial for telomere maintenance and DNA repair. The gene has two main transcripts in human cells: the 1300 amino acid isoform 3 and the 1219 amino acid isoform 1. RTEL1 isoform 3 contains a conserved C4C4-RING domain responsible for resolving the t-loop required for telomere replication. Using next-generation sequencing (NGS), RTEL1 germline variants with unknown clinical significance have been found in AA patients. Functional tests may elucidate RTEL1 variants' pathogenic role in telomere biology. Here, we describe RTEL1 heterozygous germline mutations in patients with BMF and investigate their impact in telomere maintenance. We screened 63 patients with a suggestive familial phenotype for germline mutations in peripheral blood cells using a targeted, 49 gene NGS panel. To investigate variants' impact in telomere functions, telomere length (TL) was measured by Southern blot (SB), t-circles were quantified by telomere circle assay, and single-stranded overhang was measured by non-denaturing SB. Eight patients carried novel heterozygous non-synonymous RTEL1 variants: four nucleotide changes were located in the RAD3 domain, six in the harmonin-like domain, and one in the RING domain. Clinical features and TL were heterogeneous (Table 1). The only RTEL1 variant predicted as pathogenic in silico was F1262L (c.3786 C>G) in patient 2; this mutation affects a highly conserved amino acid residue located in the RING domain, which is responsible for RTEL1 interaction with TRF2 at telomeres and t-loop unwinding. Patient 2 had very short telomeres, abnormal accumulation of t-circles, and eroded single-stranded telomeric overhangs in leukocytes, indicating a disrupted RTEL1 RING domain. To confirm observations made in clinical samples, 293T cells transfected with a plasmid carrying wild-type RTEL1-FLAG isoform 3 or its F1262L mutated version were assessed for TRF2 and FLAG co-localization in the nucleus. By confocal microscopy, wild-type RTEL1, but not mutant RTEL1 co-localized with TRF2. These findings strongly implicate RTEL1-F1262L as pathogenic, and thus the first autosomal dominant mutation in the RING domain in an AA patient. In patient 1, D743N variant in silico prediction was indeterminate, but telomeres were very short and there was a family history of typical telomeropathy (AA, liver cirrhosis, and pulmonary fibrosis) without any other suspicious germline mutations. The D743N variant is located close to the V745M variant that has been reported in a patient with dyskeratosis congenita. Increased amounts of t-circles and telomeric overhang attrition were observed in three other patients (#4, 5, and 7). While not specific for RTEL1 function, these results suggest telomere dysfunction, despite TLs in the normal range for patient 4 and 5. The RTEL1 P82L variant also appeared related to clonal evolution and leukemic progression observed in patient 5. For patients 3, 4, 6, 7, and 8, several mutations were observed in other genes concomitant to RTEL1, and a more complex genomic architecture may be the cause of patients' phenotype. A previously reported TERC variant, and a TERT variant of undetermined in silico prediction, could be pathogenic in patients 7 and 6, respectively. In these cases, RTEL1 variants may modulate disease, or represent only coincidental abnormalities. To our knowledge, this is the first report of heterozygous RTEL1 mutations in AA. We also describe a TL-independent association between RTEL1 haploinsufficiency and telomere dysfunction in humans. Haploinsufficiency of RTEL1 may disrupt DNA repair, destabilize the genome, and promote leukemogenesis by a mechanism different than typical accelerated telomere attrition associated with very short telomeres. T-circle quantification and overhang measurement may be better measures of telomere dysfunction in patients with RTEL1 variants than simple TL assessment. The combination of different functional tests was useful to the assessment of novel variants impact in telomere maintenance and DNA repair. Disclosures Fernandez Ibanez: GSK/Novartis: Research Funding. Desierto:GSK/Novartis: Research Funding. Townsley:GSK/Novartis: Research Funding. Young:GSK/Novartis: Research Funding.

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Schertzer, Michael, Laurent Jullien, André L. Pinto, Rodrigo T. Calado, Patrick Revy, and Arturo Londoño-Vallejo. "Human RTEL1 Interacts with KPNB1 (Importin β) and NUP153 and Connects Nuclear Import to Nuclear Envelope Stability in S-Phase." Cells 12, no. 24 (December 8, 2023): 2798. http://dx.doi.org/10.3390/cells12242798.

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Regulator of TElomere Length Helicase 1 (RTEL1) is a helicase required for telomere maintenance and genome replication and repair. RTEL1 has been previously shown to participate in the nuclear export of small nuclear RNAs. Here we show that RTEL1 deficiency leads to a nuclear envelope destabilization exclusively in cells entering S-phase and in direct connection to origin firing. We discovered that inhibiting protein import also leads to similar, albeit non-cell cycle-related, nuclear envelope disruptions. Remarkably, overexpression of wild-type RTEL1, or of its C-terminal part lacking the helicase domain, protects cells against nuclear envelope anomalies mediated by protein import inhibition. We identified distinct domains in the C-terminus of RTEL1 essential for the interaction with KPNB1 (importin β) and NUP153, respectively, and we demonstrated that, on its own, the latter domain can promote the dynamic nuclear internalization of peptides that freely diffuse through the nuclear pore. Consistent with putative functions exerted in protein import, RTEL1 can be visualized on both sides of the nuclear pore using high-resolution microscopy. In all, our work points to an unanticipated, helicase-independent, role of RTEL1 in connecting both nucleocytoplasmic trafficking and nuclear envelope integrity to genome replication initiation in S-phase.

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Borie, Raphael, Diane Bouvry, Vincent Cottin, Clement Gauvain, Aurélie Cazes, Marie-Pierre Debray, Jacques Cadranel, et al. "Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes." European Respiratory Journal 53, no. 2 (February 2019): 1800508. http://dx.doi.org/10.1183/13993003.00508-2018.

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Regulator of telomere length 1 (RTEL1) mutations have been evidenced in 5–9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase (TERT) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0–80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts.

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Marsh, Judith C. W., Fernanda Gutierrez-Rodrigues, James Cooper, Jie Jiang, Shreyans Gandhi, Sachiko Kajigaya, Xingmin Feng, et al. "Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms." Blood Advances 2, no. 1 (January 4, 2018): 36–48. http://dx.doi.org/10.1182/bloodadvances.2017008110.

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Key Points RTEL1 variants associate with AA, idiopathic cytopenias, and hypocellular myelodysplastic syndromes. Detailed clinical/family history, functional assays, and in silico tools are critical for interpreting the pathogenicity of RTEL1 variants.

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Kannengiesser, Caroline, Raphael Borie, Christelle Ménard, Marion Réocreux, Patrick Nitschké, Steven Gazal, Hervé Mal, et al. "HeterozygousRTEL1mutations are associated with familial pulmonary fibrosis." European Respiratory Journal 46, no. 2 (May 28, 2015): 474–85. http://dx.doi.org/10.1183/09031936.00040115.

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Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genesTERT(reverse transcriptase) andTERC(RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF withoutTERTandTERCmutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygousRTEL1mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this,RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygousRTEL1mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus,RTEL1enlarges the number of telomere-associated genes implicated in FPF.

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Ballew, Bari J., Kevin B. Jacobs, Meredith Yeager, Neelam Giri, Joseph F. Boland, Belynda D. Hicks, Laurie Burdett, Amy A. Hutchinson, Blanche P. Alter, and Sharon A. Savage. "Germline Mutations in RTEL1 cause Dyskeratosis Congenita." Blood 120, no. 21 (November 16, 2012): 515. http://dx.doi.org/10.1182/blood.v120.21.515.515.

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Abstract Abstract 515 Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome that results from impaired telomere maintenance. The classic triad (dysplastic nails, skin pigmentation, and oral leukoplakia) is diagnostic of DC but significant clinical heterogeneity can exist, even within a family. Leukocyte telomere lengths less than the first percentile for age are diagnostic of DC. Patients with DC are at high risk of bone marrow failure (BMF), myelodysplastic syndrome, cancer, pulmonary fibrosis, liver disease and other complications. Currently, germline mutations in 1 of 8 telomere biology genes (DKC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53, and CTC1) are known to cause ∼50–60% of DC cases. Our longitudinal cohort study conducts detailed medical record review and clinical examinations of patients with DC and their family members. DC is diagnosed based on the presence of the diagnostic triad or 1 of the triad plus BMF. All DC patients had telomeres <1st percentile. Patients are classified as DC-like if they have telomeres <1st percentile and other features, such as BMF or family history, suggestive of DC. All participants in this study were negative for mutations in the known DC genes. We performed whole exome sequencing (WES) on two DC families using an enriched multiplexed sequencing library (Nimblegen v2) and sequenced on an Illumina HiSeq™. Variants were removed from analyses if they did not pass quality control filters or were present more than 3 times in publically available databases (1000Genomes, ESP, Kaviar, and dbSNP). Since DC can be inherited in autosomal dominant, autosomal recessive, and X-linked manners, we evaluated all inheritance models in our families. Additionally, if healthy family members had very short telomeres, they were also evaluated as potential silent carriers, since this approach has facilitated the identification of other DC genes. Nonsynonymous variants were considered deleterious if SIFT, PolyPhen 2, and Condel predictions were consistent. Family 1 has 2 siblings with the Hoyeraal Hreidarsson syndrome (HH) variant of DC, which includes features of DC plus cerebellar hypoplasia. In that family, WES revealed autosomal dominant inheritance of a nonsense mutation in RTEL1 (Regulator of Telomere Elongation Helicase 1), p.Arg1010Stop. Their mother, who has lymphocyte telomere lengths at the 1st percentile, is a clinically silent carrier of this mutation; the severe phenotypes present in her children are likely an example of genetic anticipation. In family 2, we found 2 RTEL1 mutations, a nonsense (p.Arg998Stop) and a deleterious missense (p.Glu615Asp) mutation, that were inherited from the father and mother, respectively. One clinically healthy child inherited only the missense mutation, but has telomeres <1st percentile. The other child has HH and extremely short telomeres; he is a compound heterozygote, having inherited both the missense and nonsense mutations in RTEL1. We subsequently performed targeted sequencing of the entire RTEL1 gene in all of our mutation-negative DC (n=11) and DC-like (n=14) families. We identified missense mutations in RTEL1 in 2 additional families. Family 3 has 2 DC-like siblings, but only the proband's DNA was available for sequencing. He was heterozygous for a deleterious missense mutation (p.Ala645Thr) in a conserved helicase domain of RTEL1. In family 4, a mutation was inherited in an autosomal recessive manner by a proband with HH. This mutation is intronic except for a read-through transcript of RTEL1-TNFRSF6B, which utilizes an alternative exon 34. If translated, this variant results in the amino acid change p.Arg1264His, which is likely deleterious; if not, this mutation may affect nonsense-mediated decay or induce a regulatory change in RTEL1 expression. RTEL1 is an essential, evolutionarily conserved DNA helicase that is important for DNA replication and telomere elongation. Depletion of mRTEL1 from mouse embryonic stem cells results in telomeric loss and chromosomal instability. All individuals with germline RTEL1 mutations in this study have short telomeres, which underscores the functional importance of RTEL1 in human telomere maintenance. In summary, by employing WES followed by targeted sequencing, we discovered mutations in RTEL1 in 4 DC families, indicating that dysfunctional RTEL1 is a biologically plausible cause of DC. Disclosures: No relevant conflicts of interest to declare.

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Gandhi, Shreyans, Jie Jiang, Mariam Ibanez, Isabelle Callebaut, Judith CW Marsh, and Ghulam J. Mufti. "Heterozygous RTEL1 Variants Are Associated with Bone Marrow Failure and Abnormal Clinical Phenotype." Blood 128, no. 22 (December 2, 2016): 1043. http://dx.doi.org/10.1182/blood.v128.22.1043.1043.

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Abstract Introduction Heterozygous RTEL1 mutations have recently been described in familial pulmonary fibrosis (PF) but are not known to be associated with cytopenias or bone marrow failure (BMF), in contrast to heterozygous mutations in other telomere maintenance genes TERT, TERC and TINF2. Constitutional BMF syndromes typically present with less severe pancytopenia and it is often unclear if they have hypocellular MDS (hypoMDS) or non-severe AA (NSAA) morphologically. Methods We screened 284 patients with idiopathic AA or uncharacterised BMF and 172 patients with MDS or acute myeloid leukemia (AML) for TL and RTEL1 variants, and for the other currently known telomere gene complex (TGC) mutations, after excluding patients with Fanconi anemia, DBA or other known inherited BMF syndrome. TL was measured using a monochrome multiplex quantitative PCR method on peripheral blood mononuclear cells. Illumina Nextera-amplicon sequencing was used to screen exons of the DC genes (DKC1, TERC, TERT, RTEL1, CTC1, NHP10, NOP2, USB1, WRAP53, TINF2, PARN and ACD) by MiSeq platform. Constitutional DNA was also analysed in 10 patients (skin 9, buccal swab 1) with RTEL1 variants. A targeted gene panel of 24 genes of an Illumina Tru-Seq Custom Amplicon workflow and platform was used to identify genes frequently mutated in MDS/AML. Impact of mutations was predicted based on 3D structure information from comparative modelling for the helicase domain, comprising the HD1 and HD2 subdomains, a Fe-S cluster and an ARCH domain, and for two harmonin-like (HML) domains and a RING finger domain, located in the C-terminal regulatory region of RTEL1. Results Heterozygous RTEL1 variants were identified in 20 (4.4%) patients. RTEL1 variant allele frequency (VAF) was 45-70% consistent with heterozygous inheritance in all cases. TL was short in 18 (90%) patients, being < 1st centile in 15 and <10th centile in 3. 2 patients had normal TL, <20th centile and >50th centile, respectively. Median age was 35 years (range 18-73). 15/20 (75%) had a hypocellular BM (7 hypoMDS, 5 non-severe AA, 3 ICUS), and 1 each with RAEB1, RAEB2, CMML1, AML and isolated macrocytosis. 3 patients had abnormal karyotype: +8 (hypoMDS), -Y,+1,del(1) (hypoMDS), del7q (RAEB1). 2 other patients with hypoMDS had somatic mutations: U2AF1 (30% VAF) with ASXL1 (27% VAF); U2AF1 (43% VAF). Lung abnormalities were early PF (1), interstitial lung disease (1), and abnormal lung function with reduced TLCO (1) and an obstructive picture (1). Liver fibrosis with portal hypertension and varices and reticulate skin pigmentation were present in the patient with ILD, 2 patients had dystrophic nails, and 1 unexplained mild hepato-splenomegaly. 2 patients had familial MDS, 5 had a family history of cancers affecting first-degree relatives, and 2 had skeletal and cartilage anomalies, associated with learning difficulties in 1 patient. 8/15 patients with hypocellular BM required no treatment (5 hypoMDS and 3 NSAA), one hypoMDS had CR with ciclosporin and another underwent successful unrelated donor stem cell transplant; for NSAA, 2 received ATG with CSA, with PR followed by relapse in one, the other was lost to follow up, and 1 was androgen responsive. 16/20 (80%) patients are alive; 3 patients with RAEB or AML died of progressive disease and 1 patient with ICUS and severe constitutional features died from lymphoma 10 years after presentation. Mutations were spread throughout the entire RTEL1 sequence (summarised in Figure). 3D structure analysis predicted the missense RTEL1 mutations would result in disturbance of the FeS cluster and/or interfere with DNA binding, destabilisation of the HD1, HD2 or the ARCH sub-domains of the helicase domain, or destabilisation of inter-domain interactions. One HML1 mutation occurred in a loop opposite the putative ligand binding site and the rest in the variable regions outside the conserved domains. RTEL1 variants were associated with TERT mutations in 4 patients, of which 3 were known pathogenetic and 1 novel TERT mutation with low telomerase activity on TRAP assay confirming its pathogenetic nature. Conclusions We show for the first time that heterozygous RTEL1 mutations occur in 4.4% of patients, most commonly in young patients with a hypocellular BM, and often a family history of BMF/malignancy, and less often with high risk MDS/AML. Abnormal clinical features were present in a third of patients, some similar to but others distinct from dyskeratosis congenita. Disclosures No relevant conflicts of interest to declare.

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Simon, Rachel A., Christy M. Finke, Terra L. Lasho, Christopher T. Schmitz, Jenna A. Fernandez, Eva M. Carmona-Porquera, Mark E. Wylam, et al. "Functional Testing of Variants of Uncertain Significance in TERC, TERT,and RTEL1 from Adult Patients with Telomere Biology Disorders." Blood 142, Supplement 1 (November 28, 2023): 1365. http://dx.doi.org/10.1182/blood-2023-190153.

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INTRODUCTION Telomere biology disorders (TBDs) are multisystem diseases caused by accelerated telomere shortening that can present with bone marrow failure and pulmonary fibrosis, among other abnormalities. TBD diagnosis is considered when average blood telomere length (TL) measured by clinical flowFISH is <1 st percentile and/or a pathogenic variant in telomere maintenance genes (most commonly TERT, TERC, RTEL1) is identified. Pathogenic variants in genes coding for the telomerase protein ( TERT) and RNA component ( TERC) decrease telomerase activity. Similarly, variants in RTEL1 result in defective unwinding of the t-loop at telomere ends, increasing the levels of free t-circles in cells. Variants in these genes are often classified as variants of uncertain significance (VUSs by ACMG criteria) with additional efforts needed for variant curation. To address this, we describe results of functional testing performed in TBD patients with VUSs involving TERT, TERC, and RTEL1. METHODS TBD suspected patients were identified through the Pre-Myeloid Cancer and Bone Marrow Failure Clinic (Mayo Clinic) where they underwent clinical flowFISH and genetic testing for TBD related genes. Informed consent was obtained with approval from the Mayo Clinic Institutional Review Board. Viable peripheral blood and bone marrow samples were collected along with age matched healthy volunteers. Telomerase activity was measured in samples with TERT and TERC variants through telomeric repeat amplification protocol (TRAP) assays using the TRAPeze XL Telomerase Detection Kit (MilliporeSigma) following manufacturer instructions. HCT116 cells were used as positive controls while heat inactivated samples served as negative controls. Fluorescence was measured in a SpectraMax plate reader. Percentage of total product generated (TPG) relative to healthy age matched controls was calculated. T-circle detection assays were used on RTEL1 samples based on the protocol by Zhang et al. (2017). Final southern blotting was completed using the TeloTAGGG Telomere Length Assay Kit (Roche), and t-circle bands were visualized in a c600 GEL Imaging System (Azure Biosystems). RESULTS Ten patients (mean age = 53 years (27-71), 50% female) were included in our study. Patients 1 to 5 presented VUS in TERT (n=4) or TERC (n=1) and TL <1 st percentile in lymphocytes and/or granulocytes. Patient 6 carried a known pathogenic variant in RTEL1 and was included as a positive control. Patients 7 to 9 with RTEL1 variants presented TL close to the 10 th or between the 1 st-10 th percentile. No TL results were available for patient 10 but was tested due to the presence of a VUS in RTEL1 (Table 1). Similarly, while patient 7 carried a likely pathogenic variant, it was tested due to presenting lymphocyte TL between the 1 st-10 th percentile. TRAP results indicated decreased telomerase activity compared to age matched controls in all samples with TERT and TERC variants suggesting a pathogenic effect (52.%, 10.7%, 48.7%, 4.4% and 5.2% of TPG compared to age matched controls, respectively) (Table 1). On the other hand, t-circles were only seen in patient 6 (Figure 2). DISCUSSION We used TRAP and t-circle assays to explore the telomerase activity and presence of t-circles in patient samples with TERT/TERC and RTEL1 variants. In the case of TERT/TERC, we observed a reduction of telomerase activity in all samples. Together with blood TL below the 1 st percentile, this suggests that these variants are indeed deleterious (Table 1). However, since patient 4 presented two TERT VUSs, additional testing is needed to conclude how each variant impacts telomerase activity independently. In regard to RTEL1 variants, we observed t-circles in patient 6 as expected. No t-circles could be seen on all remaining samples, including patient 7 who carried a variant classified as likely pathogenic (Figure 1). This in-frame deletion has been described once in a TBD family (Cogan et al. 2015) but was not functionally tested. This result, together with the borderline TL seen in this patient, may suggest that some compensatory mechanism exists on this sample, or that the deleterious effect of the variant is not strong enough to be detected by our assay. Further studies are currently ongoing by our group to validate these results using a cell-based transfection disease model. In summary, we show that functional testing can be a helpful tool to determine pathogenicity of VUSs in TERT/TERC and RTEL1.

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&NA;. "RTEL1: the protector of the genome." Oncology Times UK 5, no. 11 (November 2008): 4. http://dx.doi.org/10.1097/01434893-200811000-00004.

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Wang, Tuo, Yan Zhang, Bo Cui, Maode Wang, Ya Li, and Ke Gao. "miR-4530 inhibits the malignant biological behaviors of human glioma cells by directly targeting RTEL1." Acta Biochimica et Biophysica Sinica 52, no. 12 (November 17, 2020): 1394–403. http://dx.doi.org/10.1093/abbs/gmaa126.

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Abstract Human glioma is the most common primary brain tumor and is associated with high morbidity and mortality. Aberrant expressions of microRNAs (miRNAs) are involved in glioma progression. In the present study, we aimed to elucidate the roles of miR-4530 in the pathogenesis of gliomas. miR-4530 expression was examined in human glioma clinical tissues and cell lines including U251 and T98G. The target gene of miR-4530, RTEL1, was predicted with online tools and validated by luciferase reporter assay. Lentivirus infection, transfection of plasmids, and miRNA mimics were used to manipulate gene expression. Cell proliferation was determined using the CCK-8 method, and migration and invasion assays were determined with transwell experiments. Colony formation was measured by crystal violet staining, while apoptosis was determined by Annexin V/PI staining. The anti-tumor effects of miR-4530 were evaluated in nude mice xenografted using U251 cells. Our results showed that miR-4530 was significantly down-regulated in human glioma tissues and cell lines. miR-4530 over-expression inhibited the malignant behaviors of U251 and T98G cells, including reduced proliferation, diminished colony formation, migration and invasion, and increased apoptosis. Further mechanistic investigations revealed that RTEL1 is a direct functional target of miR-4530 in gliomas, and its over-expression remarkably reverses the effects of miR-4530 mimics on inhibiting these malignant behaviors. In addition, miR-4530 over-expression inhibited the growth of xenografted U251 glioma in nude mice. Therefore, miR-4530 acts as a tumor-suppressor gene and inhibits the malignant biological behaviors of human glioma cells, which is associated with directly targeting RTEL1. The miR-4530/RTEL1 axis is a potential therapeutic target for gliomas.

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Touzot, Fabien, Laetitia Kermasson, Laurent Jullien, Despina Moshous, Christelle Ménard, Aydan Ikincioğullari, Figen Doğu, et al. "Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations." Blood Advances 1, no. 1 (November 22, 2016): 36–46. http://dx.doi.org/10.1182/bloodadvances.2016001313.

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Seshadri, Nivedita, Sumit Sandhu, Xiaoli Wu, Wenjun Liu, and Hao Ding. "Generation of an Rtel1-CreERT2 knock-in mouse model for lineage tracing RTEL1+ stem cells during development." Transgenic Research 27, no. 6 (September 8, 2018): 571–78. http://dx.doi.org/10.1007/s11248-018-0093-y.

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Juge, Pierre-Antoine, Raphaël Borie, Caroline Kannengiesser, Steven Gazal, Patrick Revy, Lidwine Wemeau-Stervinou, Marie-Pierre Debray, et al. "Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis." European Respiratory Journal 49, no. 5 (May 2017): 1602314. http://dx.doi.org/10.1183/13993003.02314-2016.

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Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53–6.12; p=9.45×10−4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10−2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.

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Vannier, Jean-Baptiste, Grzegorz Sarek, and Simon J. Boulton. "RTEL1: functions of a disease-associated helicase." Trends in Cell Biology 24, no. 7 (July 2014): 416–25. http://dx.doi.org/10.1016/j.tcb.2014.01.004.

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Frizzell, Aisling, Jennifer H. G. Nguyen, Mark I. R. Petalcorin, Katherine D. Turner, Simon J. Boulton, Catherine H. Freudenreich, and Robert S. Lahue. "RTEL1 Inhibits Trinucleotide Repeat Expansions and Fragility." Cell Reports 6, no. 5 (March 2014): 827–35. http://dx.doi.org/10.1016/j.celrep.2014.01.034.

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Kropski, Jonathan A., and James E. Loyd. "Telomeres revisited: RTEL1 variants in pulmonary fibrosis." European Respiratory Journal 46, no. 2 (July 31, 2015): 312–14. http://dx.doi.org/10.1183/13993003.00710-2015.

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Frizzell, Aisling, Jennifer H. G. Nguyen, Mark I. R. Petalcorin, Katherine D. Turner, Simon J. Boulton, Catherine H. Freudenreich, and Robert S. Lahue. "RTEL1 Inhibits Trinucleotide Repeat Expansions and Fragility." Cell Reports 16, no. 7 (August 2016): 2047. http://dx.doi.org/10.1016/j.celrep.2016.07.072.

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Liu, Yanhong, Sanjay Shete, Carol J. Etzel, Michael Scheurer, George Alexiou, Georgina Armstrong, Spyros Tsavachidis, et al. "Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 Genes Involved in the Double-Strand Break Repair Pathway Predict Glioblastoma Survival." Journal of Clinical Oncology 28, no. 14 (May 10, 2010): 2467–74. http://dx.doi.org/10.1200/jco.2009.26.6213.

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Purpose Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment. Patients and Methods Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; ≤ 12 months) and long-term survivors (LTS; ≥ 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs. Results We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients ≥ 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years). Conclusion Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.

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Aklilu, Behailu B., François Peurois, Carole Saintomé, Kevin M. Culligan, Daniela Kobbe, Catherine Leasure, Michael Chung, et al. "Functional Diversification of Replication Protein A Paralogs and Telomere Length Maintenance in Arabidopsis." Genetics 215, no. 4 (June 12, 2020): 989–1002. http://dx.doi.org/10.1534/genetics.120.303222.

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Replication protein A (RPA) is essential for many facets of DNA metabolism. The RPA gene family expanded in Arabidopsis thaliana with five phylogenetically distinct RPA1 subunits (RPA1A-E), two RPA2 (RPA2A and B), and two RPA3 (RPA3A and B). RPA1 paralogs exhibit partial redundancy and functional specialization in DNA replication (RPA1B and RPA1D), repair (RPA1C and RPA1E), and meiotic recombination (RPA1A and RPA1C). Here, we show that RPA subunits also differentially impact telomere length set point. Loss of RPA1 resets bulk telomeres at a shorter length, with a functional hierarchy for replication group over repair and meiosis group RPA1 subunits. Plants lacking RPA2A, but not RPA2B, harbor short telomeres similar to the replication group. Telomere shortening does not correlate with decreased telomerase activity or deprotection of chromosome ends in rpa mutants. However, in vitro assays show that RPA1B2A3B unfolds telomeric G-quadruplexes known to inhibit replications fork progression. We also found that ATR deficiency can partially rescue short telomeres in rpa2a mutants, although plants exhibit defects in growth and development. Unexpectedly, the telomere shortening phenotype of rpa2a mutants is completely abolished in plants lacking the RTEL1 helicase. RTEL1 has been implicated in a variety of nucleic acid transactions, including suppression of homologous recombination. Thus, the lack of telomere shortening in rpa2a mutants upon RTEL1 deletion suggests that telomere replication defects incurred by loss of RPA may be bypassed by homologous recombination. Taken together, these findings provide new insight into how RPA cooperates with replication and recombination machinery to sustain telomeric DNA.

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Walne, Amanda J., Tom Vulliamy, Michael Kirwan, Vincent Plagnol, and Inderjeet Dokal. "Constitutional Mutations in RTEL1 Cause Severe Dyskeratosis Congenita." American Journal of Human Genetics 92, no. 3 (March 2013): 448–53. http://dx.doi.org/10.1016/j.ajhg.2013.02.001.

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Barber, Louise J., Jillian L. Youds, Jordan D. Ward, Michael J. McIlwraith, Nigel J. O'Neil, Mark I. R. Petalcorin, Julie S. Martin, et al. "RTEL1 Maintains Genomic Stability by Suppressing Homologous Recombination." Cell 135, no. 2 (October 2008): 261–71. http://dx.doi.org/10.1016/j.cell.2008.08.016.

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Villeneuve, Anne M. "Ensuring an Exit Strategy: RTEL1 Restricts Rogue Recombination." Cell 135, no. 2 (October 2008): 213–15. http://dx.doi.org/10.1016/j.cell.2008.10.003.

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Coskun, C., S. Unal, and N. Akarsu. "A rare variant of dyskeratosis congenita: RTEL1 defect." Hematology, Transfusion and Cell Therapy 42 (October 2020): 68–69. http://dx.doi.org/10.1016/j.htct.2020.09.122.

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Wajda, Benjamin G., Alexander S. Platt, April D. Ingram, and Anna L. Ells. "Retinal Findings of a Unique RTEL1 Mutation in Dyskeratosis Congenita." Journal of VitreoRetinal Diseases 1, no. 6 (September 13, 2017): 411–14. http://dx.doi.org/10.1177/2474126417730718.

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We describe the retinal manifestations of a patient with a unique mutation of the Regulator of telomere length 1 ( RTEL1) gene resulting in dyskeratosis congenita (DC), a rare, fatal, inherited disease. A 4-year-old boy with DC was referred for ophthalmology consult by his attending hematologist and underwent a complete ophthalmic examination, including wide-field fundus imaging and fluorescein angiography. The patient was found to have bilateral retinal vasculopathy and extensive microvascular abnormalities in addition to avascular regions in the temporal peripheral retina. He received multiple pan-retinal photocoagulation treatments in both eyes. Our case highlights the importance of ophthalmic screening and fluorescein angiography and the potential need for timely laser photocoagulation for sight-threatening retinopathy in patients with DC.

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Uringa, Evert-Jan, Kathleen Lisaingo, Hilda A. Pickett, Julie Brind'Amour, Jan-Hendrik Rohde, Alex Zelensky, Jeroen Essers, and Peter M. Lansdorp. "RTEL1 contributes to DNA replication and repair and telomere maintenance." Molecular Biology of the Cell 23, no. 14 (July 15, 2012): 2782–92. http://dx.doi.org/10.1091/mbc.e12-03-0179.

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Telomere maintenance and DNA repair are important processes that protect the genome against instability. mRtel1, an essential helicase, is a dominant factor setting telomere length in mice. In addition, mRtel1 is involved in DNA double-strand break repair. The role of mRtel1 in telomere maintenance and genome stability is poorly understood. Therefore we used mRtel1-deficient mouse embryonic stem cells to examine the function of mRtel1 in replication, DNA repair, recombination, and telomere maintenance. mRtel1-deficient mouse embryonic stem cells showed sensitivity to a range of DNA-damaging agents, highlighting its role in replication and genome maintenance. Deletion of mRtel1 increased the frequency of sister chromatid exchange events and suppressed gene replacement, demonstrating the involvement of the protein in homologous recombination. mRtel1 localized transiently at telomeres and is needed for efficient telomere replication. Of interest, in the absence of mRtel1, telomeres in embryonic stem cells appeared relatively stable in length, suggesting that mRtel1 is required to allow extension by telomerase. We propose that mRtel1 is a key protein for DNA replication, recombination, and repair and efficient elongation of telomeres by telomerase.

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Kotsantis, Panagiotis, Sandra Segura-Bayona, Pol Margalef, Paulina Marzec, Phil Ruis, Graeme Hewitt, Roberto Bellelli, et al. "RTEL1 Regulates G4/R-Loops to Avert Replication-Transcription Collisions." Cell Reports 33, no. 12 (December 2020): 108546. http://dx.doi.org/10.1016/j.celrep.2020.108546.

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Campos, Lillian V., Sabrina X. Van Ravenstein, Emma J. Vontalge, Briana H. Greer, Darren R. Heintzman, Tamar Kavlashvili, W. Hayes McDonald, Kristie Lindsey Rose, Brandt F. Eichman, and James M. Dewar. "RTEL1 and MCM10 overcome topological stress during vertebrate replication termination." Cell Reports 42, no. 2 (February 2023): 112109. http://dx.doi.org/10.1016/j.celrep.2023.112109.

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Wu, Zhuochao, Zhicheng Gong, Chaoqun Li, and Zhaohui Huang. "RTEL1 is upregulated in colorectal cancer and promotes tumor progression." Pathology - Research and Practice 252 (December 2023): 154958. http://dx.doi.org/10.1016/j.prp.2023.154958.

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Cardoso, Shirleny R., Alicia C. M. Ellison, Amanda J. Walne, David Cassiman, Manoj Raghavan, Bhuvan Kishore, Philip Ancliff, et al. "Myelodysplasia and liver disease extend the spectrum of RTEL1 related telomeropathies." Haematologica 102, no. 8 (May 11, 2017): e293-e296. http://dx.doi.org/10.3324/haematol.2017.167056.

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Olivier, Margaux, Cyril Charbonnel, Simon Amiard, Charles I. White, and Maria E. Gallego. "RAD51 and RTEL1 compensate telomere loss in the absence of telomerase." Nucleic Acids Research 46, no. 5 (January 13, 2018): 2432–45. http://dx.doi.org/10.1093/nar/gkx1322.

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Takedachi, A., E. Despras, S. Scaglione, R. Guérois, J. H. Guervilly, M. Blin, S. Audebert, et al. "SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations." Nature Structural & Molecular Biology 27, no. 5 (May 2020): 438–49. http://dx.doi.org/10.1038/s41594-020-0419-3.

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Le Guen, Tangui, Laurent Jullien, Mike Schertzer, Axelle Lefebvre, Laetitia Kermasson, Jean-Pierre de Villartay, Arturo Londoño-Vallejo, and Patrick Revy. "RTEL1, une hélicase de l’ADN essentielle à la stabilité du génome." médecine/sciences 29, no. 12 (December 2013): 1138–44. http://dx.doi.org/10.1051/medsci/20132912018.

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Porreca, Rosa M., Galina Glousker, Aya Awad, Maria I. Matilla Fernandez, Anne Gibaud, Christian Naucke, Scott B. Cohen, et al. "Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension." Nucleic Acids Research 46, no. 9 (March 7, 2018): 4533–45. http://dx.doi.org/10.1093/nar/gky173.

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Yamaguchi, Hiroki, Hirotoshi Sakaguchi, Kenichi Yoshida, Miharu Yabe, Hiromasa Yabe, Yusuke Okuno, Hideki Muramatsu, et al. "The Clinical and Genetic Features of Dyskeratosis Congenita, Cryptic Dyskeratosis Congenita, and Hoyeraal-Hreidarsson Syndrome in Japan." Blood 124, no. 21 (December 6, 2014): 1608. http://dx.doi.org/10.1182/blood.v124.21.1608.1608.

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Abstract Background: Dyskeratosis congenita (DKC) is an inherited bone marrow failure syndrome typified by reticulated skin pigmentation, nails dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is considered to be a severe form of DKC. Unconventional forms of DKC, which develop slowly in adulthood without physical anomalies characteristic to DKC, have been reported. Clinical and genetic features of DKC have been investigated in Caucasian, Black, and Hispanic populations, but never in Asian populations. Therefore, the present study aimed to determine the clinical and genetic features of DKC, HHS, and cryptic DKC among Japanese patients. Methods: We analyzed 16 patients diagnosed with DKC, 3 patients with HHS, and 21 patients with cryptic DKC between 2003 and 2014 in Japan. Telomere length was measured by Southern blot and/or flow-fluorescence in situ hybridization methods. Mutation analyses were performed using direct sequencing for DKC1, TERC, TERT, NOP10, NHP2, and TINF2. In some patients, we also analyzed the exon sequence and genome copy number using a next-generation sequencer. Results: Age at diagnosis was significantly older in the following order: HHS, DKC, and cryptic DKC (p<0.001). Twenty-five percent of DKC and HHS patients, and 33% of cryptic DKC patients, were women. Two DKC patients and six cryptic DKC patients had a family history. Characteristic findings of DKC included nail dystrophy (93.75%), reticulated skin pigmentation (87.5%), and lingual leukoplakia (81.3%), with 11/15 (68.8%) patients showing all three physical abnormalities. Characteristic findings of HHS were reticulated skin pigmentation 100%), nail dystrophy (66.7%), and lingual leukoplakia (33.3%); none of the patients had all three abnormalities. Regarding peripheral blood anomalies in DKC patients, peripheral blood count results at diagnosis revealed a marked reduction in platelet count among the three types of blood cells assessed: 7/16 (43.8%) patients had a platelet count ≤20000/µl, whereas only 1/16 (6.3%) patient had a neutrophil count ≤1000/µl or Hb ≤7g/dl. Telomere length analysis revealed that telomere length was shortened in 6/7 (85.7%) DKC patients, and all HHS and cryptic DKC patients. Mutations of telomere regulated genes were found in 11/16 (68.7%) DKC patients (DKC1 mutations in 5 patients, TINF2 mutations in 3 patients, TERT mutations in 2 patients, and TERC mutations in 1 patient). Among these, those harboring the homozygous TERT c.1002_1004del mutation showed a large deletion in the region encoding the TERT gene in one allele on chromosome number 5 by SNP array analysis. This is the first report of a large deletion in the TERT gene. With respect to HHS patients, no causative gene mutation could be identified for any of the patients. With respect to cryptic DKC patients, 11/21 (52.4%) patients had gene mutations (TERT mutations in 5 patients, TINF2 mutations in 3 patients, RTEL1 mutations in 2 patients (1 family), and TERC mutations in 1 patient). Those with RTEL1 mutations had mutations of both alleles, whereas those with the other mutations had heterozygous mutations. While the RTEL1 mutation is often discovered in HHS patients in the form of autosomal recessive inheritance, these two patients did not have apparent physical abnormalities characteristic to DKC, and thus represent the first case of cryptic DKC involving RTEL1 mutations. Immunosuppressive agents such as cyclosporine and steroids were administered to five patients, but no apparent efficacy was observed. Anabolic steroid hormones were also administered to five patients, and mild improvement in anemia was observed in one DKC patient, and mild improvement in reduced platelet count in one HHS patient. Hematopoietic stem cell transplantation was performed in eight patients, resulting in long-term survival in six of these patients (post-transplantation 10-year survival rate, 58.3%). Conclusions: The present study is the first to address DKC, HHS, and cryptic DKC in Japanese people, an Asian race. We found marked reductions in platelet counts in DKC patients in blood tests at diagnosis, a high prevalence of TINF2 mutations as the causative genetic mutation, and the existence of DKC patients with large deletions in the TERT gene and cryptic DKC patients with RTEL1 mutations on both alleles. Disclosures No relevant conflicts of interest to declare.

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Jalas, Chaim, Anastasia Fedick, Bari J. Ballew, Blanche P. Alter, Neelam Giri, Simon Boulton, Kenneth Offit, John Petrini, Nathan Treff, and Sharon A. Savage. "Higher Than Expected Carrier Frequency Of The Dyskeratosis Congenita RTEL1 p.Arg1264His recessive Founder In Individuals Of Ashkenazi Jewish Ancestry." Blood 122, no. 21 (November 15, 2013): 1228. http://dx.doi.org/10.1182/blood.v122.21.1228.1228.

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Abstract Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure syndrome (IBMFS) in which germline mutations in telomere biology genes account for approximately 70% of known families. DC is clinically diagnosed by the presence of the triad of nail dysplasia, lacy skin pigmentation, and oral leukoplakia. However, not all patients have the triad and multiple other medical problems may include, stenosis of the esophagus, urethra and/or lacrimal ducts, avascular necrosis of the hips or shoulders, developmental delay, head and neck squamous cell cancer, and/or leukemia. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients have features of DC but also have microcephaly, cerebellar hypoplasia, and intrauterine growth retardation, and may present with severe immunodeficiency and enteropathy. Telomere lengths (in blood leukocyte subsets analyzed by flow FISH) less than the 1st percentile for age are diagnostic of any form of DC, including HH. We identified a germline autosomal recessive (AR) mutation (p.Arg1264His) in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The minor allele frequency of this variant is ∼0.0001 in public databases of 9600 individuals. The affected individuals in these families are homozygous for this mutation, which affects three isoforms of RTEL1. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In both families, each parent was a healthy, heterozygous carrier of one mutant allele. Haplotypes were reconstructed from twelve common SNPs based on allele sharing in the unaffected siblings and parents. No recombinants were seen in either family and the segregating risk haplotype was identical in affected individuals from both families. Thus, p.Arg1264His is carried on a common haplotype, likely from a common AJ founder. We determined the carrier frequency of the p.Arg1264His mutation, as well as three other mutations, p.Gly763Val, p.Met516Ile and p.Arg998Ter, which were recently reported and possibly found in individuals of AJ ancestry. DNA was derived from 1,048 self-described AJ individuals enrolled in the Dor Yeshorim program. Consent form information included that patient material would be used for clinical testing and that excess material would be de-identified and used for research purposes. The mutations were genotyped by TaqMan assays and heterozygous carrier samples were confirmed by Sanger sequencing with stringent quality control. No individuals in this study carried the p.Gly763Val or p.Arg998Ter minor alleles. Two individuals (0.19%) were carriers of the p.Met516Ile mutation. Notably, 1% (10 of 1,032) of AJ individuals in this study were carriers of the p.Arg1264His mutation in RTEL1. This carrier frequency of 1 in 100 is similar to that of the FANCC AJ mutation and many other FA founder populations, such as FANCA in South African Afrikaners, Spanish Gypsies, Brazilians, Tunisians, and Moroccans, as well as FANCG in Sub-Saharan Blacks, and BRCA2 (FANCD1) in the US general population. A carrier frequency of 1 in 100 is similar to that of genetic disorders found in the AJ population recommended for screening by the American College of Medical Genetics. Based on this, we suggest that genetic counseling and RTEL1 p.Arg1264His carrier screening for the HH variant of DC be offered to individuals of AJ ancestry. Disclosures: No relevant conflicts of interest to declare.

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Lansdorp, Peter, and Niek van Wietmarschen. "Helicases FANCJ, RTEL1 and BLM Act on Guanine Quadruplex DNA in Vivo." Genes 10, no. 11 (October 31, 2019): 870. http://dx.doi.org/10.3390/genes10110870.

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Guanine quadruplex (G4) structures are among the most stable secondary DNA structures that can form in vitro, and evidence for their existence in vivo has been steadily accumulating. Originally described mainly for their deleterious effects on genome stability, more recent research has focused on (potential) functions of G4 structures in telomere maintenance, gene expression, and other cellular processes. The combined research on G4 structures has revealed that properly regulating G4 DNA structures in cells is important to prevent genome instability and disruption of normal cell function. In this short review we provide some background and historical context of our work resulting in the identification of FANCJ, RTEL1 and BLM as helicases that act on G4 structures in vivo. Taken together these studies highlight important roles of different G4 DNA structures and specific G4 helicases at selected genomic locations and telomeres in regulating gene expression and maintaining genome stability.

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Ziv, Alma, Lael Werner, Liza Konnikova, Aya Awad, Tim Jeske, Maximilian Hastreiter, Vanessa Mitsialis, et al. "An RTEL1 Mutation Links to Infantile-Onset Ulcerative Colitis and Severe Immunodeficiency." Journal of Clinical Immunology 40, no. 7 (July 24, 2020): 1010–19. http://dx.doi.org/10.1007/s10875-020-00829-z.

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Adel Fahmideh, M., C. Lavebratt, J. Schüz, M. Rösli, T. Tynes,, M. A. Grotzer, C. Johansen, et al. "1055 CCDC26, CDKN2BAS, RTEL1, and TERT polymorphisms in pediatric brain tumor susceptibility." European Journal of Cancer 51 (September 2015): S163. http://dx.doi.org/10.1016/s0959-8049(16)30481-6.

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Bellelli, Roberto, Jillian Youds, Valerie Borel, Jennifer Svendsen, Visnja Pavicic-Kaltenbrunner, and Simon J. Boulton. "Synthetic Lethality between DNA Polymerase Epsilon and RTEL1 in Metazoan DNA Replication." Cell Reports 31, no. 8 (May 2020): 107675. http://dx.doi.org/10.1016/j.celrep.2020.107675.

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Rong, Hao, Xue He, Linhao Zhu, Xikai Zhu, Longli Kang, Li Wang, Yongjun He, Dongya Yuan, and Tianbo Jin. "Association between regulator of telomere elongation helicase1 (RTEL1) gene and HAPE risk." Medicine 96, no. 39 (September 2017): e8222. http://dx.doi.org/10.1097/md.0000000000008222.

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Pathak, Gita A., Frank R. Wendt, Daniel F. Levey, Adam P. Mecca, Christopher H. van Dyck, Joel Gelernter, and Renato Polimanti. "Pleiotropic effects of telomere length loci with brain morphology and brain tissue expression." Human Molecular Genetics 30, no. 14 (April 7, 2021): 1360–70. http://dx.doi.org/10.1093/hmg/ddab102.

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Abstract Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. Although telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively, with brain morphology measures for 101 T1-magnetic resonance imaging-based region of interests (n = 21 821). The posterior probability (>90%) was observed for ‘fourth ventricle’, ‘gray matter’ and ‘cerebellar vermal lobules I–IV’ volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = four genes; EUR = five genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (P ≤ 2.47 × 10−6). Integrating chromatin profiles with LTL-single nucleotide polymorphisms identified 45 genes (EUR) and 79 genes (EAS) (P ≤ 9.78×10−7). We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes—GPR37, OBFC1 and RTEL1/RTEL1-TNFRSF6B—show convergent evidence of pleiotropy with brain morphology, gene and methylation expression and chromatin association. Mapping gene functions to drug–gene interactions, we identified process ‘transmission across chemical synapses’ (P < 2.78 × 10−4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.

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Delgado, Dayana A., Chenan Zhang, Lin S. Chen, Jianjun Gao, Shantanu Roy, Justin Shinkle, Mekala Sabarinathan, et al. "Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal." Journal of Medical Genetics 55, no. 1 (November 18, 2017): 64–71. http://dx.doi.org/10.1136/jmedgenet-2017-104922.

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BackgroundLeucocyte telomere length (TL) is a potential biomarker of ageing and risk for age-related disease. Leucocyte TL is heritable and shows substantial differences by race/ethnicity. Recent genome-wide association studies (GWAS) report ~10 loci harbouring SNPs associated with leucocyte TL, but these studies focus primarily on populations of European ancestry.ObjectiveThis study aims to enhance our understanding of genetic determinants of TL across populations.MethodsWe performed a GWAS of TL using data on 5075 Bangladeshi adults. We measured TL using one of two technologies (qPCR or a Luminex-based method) and used standardised variables as TL phenotypes.ResultsOur results replicate previously reported associations in the TERC and TERT regions (P=2.2×10−8 and P=6.4×10−6, respectively). We observed a novel association signal in the RTEL1 gene (intronic SNP rs2297439; P=2.82×10−7) that is independent of previously reported TL-associated SNPs in this region. The minor allele for rs2297439 is common in South Asian populations (≥0.25) but at lower frequencies in other populations (eg, 0.07 in Northern Europeans). Among the eight other previously reported association signals, all were directionally consistent with our study, but only rs8105767 (ZNF208) was nominally significant (P=0.003). SNP-based heritability estimates were as high as 44% when analysing close relatives but much lower when analysing distant relatives only.ConclusionsIn this first GWAS of TL in a South Asian population, we replicate some, but not all, of the loci reported in prior GWAS of individuals of European ancestry, and we identify a novel second association signal at the RTEL1 locus.

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Krysiak, Kilannin, Meagan A. Jacoby, Zachary L. Skidmore, Arpad M. Danos, Michelle O'Laughlin, Eric J. Duncavage, Matthew J. Walter, Malachi Griffith, Obi L. Griffith, and Lukas D. Wartman. "Deleterious Germline Mutations in Telomere Maintenance Genes Identified in a Subset of Patients with Myelodysplastic Syndrome and Idiopathic Pulmonary Fibrosis." Blood 128, no. 22 (December 2, 2016): 4306. http://dx.doi.org/10.1182/blood.v128.22.4306.4306.

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Abstract The myelodysplastic syndromes (MDS) are the most common cause of bone marrow failure in adults, with an incidence of 40,000 cases per year. Next-generation sequencing of candidate genes has led to major advances in the description of the genetic landscape of MDS, identifying recurrently mutated genes and cellular pathways involved in disease pathogenesis. However, use of targeted panels indicates more comprehensive, unbiased sequencing techniques may yet identify additional recurrently mutated genes or cellular pathways important in MDS. Diseases caused by defects in telomere maintenance (telomeropathies) are variable in clinical and genetic presentation but often involve bone marrow failure. We hypothesized that acquired mutations in telomerase maintenance genes may be a recurrent event in MDS. This is significant as identification of recurrent somatic mutations in telomerase maintenance genes would provide further insight into MDS pathogenesis and identify a potential druggable pathway for MDS patients, as novel agents targeting the telomerase pathway are currently in clinical development. First, we identified three adults who presented in middle age with MDS and idiopathic pulmonary fibrosis (IPF), two of which also had a family history of IPF. All three patients had shortened telomeres (<1st centile), but no mutations detected in the telomerase pathway genes TERC, TERT, TINF2, or DKC2. In order to identify inherited and/or acquired genetic mutations affecting telomere biology, we performed exome sequencing on paired whole bone marrow (tumor) and skin (comparator/germline) samples from each patient. In patient 1 (see Table), we identified a heterozygous, inherited frameshift variant in RTEL1, (R132fs, not previously reported), a helicase required for telomere maintenance that has not been reported in MDS. Compound heterozygous mutations in RTEL1 have been implicated in Hoyeral-Hreiderson syndrome, and recent work showed ~5% of patients with familial IPF have heterozygous germline RTEL1 mutations (Cogan J.D. et al., Am J Resp Crit Care Med, 2015 and Stuart B.D. et al., Nat Genet, 2015). In patient 2, we identified a heterozygous inherited missense variant in ACD (V484I), a component of the telomerase shelterin complex also implicated in Hoyeral-Hreiderson syndrome that is not a common population variant (absent from 1000 genomes, the Exome Sequencing Project, and dbSNP). Analysis of constitutional alterations using the exome data from patient 3, did not identify an obvious causative variant; thus, whole genome sequencing is ongoing. These data show that inherited telomerase maintenance gene variants are found in patients with MDS and IPF. Next, to determine if telomerase complex genes were recurrently mutated in an unselected, de novo MDS population, we performed targeted next-generation sequencing of telomerase maintenance genes (15 genes) combined with sequencing of 335 myeloid malignancy-associated genes in 96 paired tumor/skin samples from MDS patients. Somatic variants were identified in the tumor compared to the paired skin using the Genome Modeling System, as previously reported (Griffith M. et al., PLoS Comput Biol. 2015). As expected, somatic analysis identified mutations in recurrently mutated MDS genes such as U2AF1, ASXL1, TET2, TP53 and others. A single, likely deleterious somatic inversion involving exon 9 of RTEL1 was identified; however, somatic analysis for telomere maintenance gene mutations was otherwise unremarkable. Evaluation of these genes for germline variants identified rare (ExAC allele frequency < 0.0007), apparently heterozygous, in-frame and frame-shift deletion variants affecting CTC1 (n=2), NOP10 (n=1) and TERT (n=1) in 4 individuals. The two CTC1 frame shift variants have been previously described in multiple patients with pediatric telomeropathies resulting from compound heterozygous mutations in CTC1. Additional heterozygous missense mutations previously associated with aplastic anemia were identified in 2 other individuals but are of uncertain significance. Collectively, these results indicate that germline mutations in telomere maintenance genes, other than TERT and TERC, underlie genetic predisposition for MDS and IPF in a subset of patients, which has not been previously appreciated, but are rare events in de novo MDS. Table Table. Disclosures Jacoby: Sunesis: Research Funding; Quintiles: Consultancy; Celgene: Speakers Bureau.

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Yan, Shouchun, Ridong Xia, Tianbo Jin, Hui Ren, Hua Yang, Jing Li, Mengdan Yan, Yuanyuan Zhu, and Mingwei Chen. "RTEL1 polymorphisms are associated with lung cancer risk in the Chinese Han population." Oncotarget 7, no. 43 (September 28, 2016): 70475–80. http://dx.doi.org/10.18632/oncotarget.12297.

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Gu, Cheng-Yuan, Sheng-Ming Jin, Xiao-Jian Qin, Yao Zhu, Dai Bo, Guo-Wen Lin, Guo-Hai Shi, and Ding-Wei Ye. "Genetic variants in RTEL1 influencing telomere length are associated with prostate cancer risk." Journal of Cancer 10, no. 24 (2019): 6170–74. http://dx.doi.org/10.7150/jca.35917.

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Cai, Yi, Chaosheng Zeng, Qingjie Su, Jingxia Zhou, Pengxiang Li, Mingming Dai, Desheng Wang, and Faqing Long. "Association of RTEL1 gene polymorphisms with stroke risk in a Chinese Han population." Oncotarget 8, no. 70 (December 5, 2017): 114995–5001. http://dx.doi.org/10.18632/oncotarget.22980.

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Vannier, J. B., S. Sandhu, M. I. Petalcorin, X. Wu, Z. Nabi, H. Ding, and S. J. Boulton. "RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication." Science 342, no. 6155 (October 10, 2013): 239–42. http://dx.doi.org/10.1126/science.1241779.

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Takedachi, A., E. Despras, S. Scaglione, R. Guérois, J. H. Guervilly, M. Blin, S. Audebert, et al. "Publisher Correction: SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations." Nature Structural & Molecular Biology 27, no. 6 (May 14, 2020): 604. http://dx.doi.org/10.1038/s41594-020-0447-z.

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Takedachi, A., E. Despras, S. Scaglione, R. Guérois, J. H. Guervilly, M. Blin, S. Audebert, et al. "Author Correction: SLX4 interacts with RTEL1 to prevent transcription-mediated DNA replication perturbations." Nature Structural & Molecular Biology 27, no. 6 (May 14, 2020): 603. http://dx.doi.org/10.1038/s41594-020-0448-y.

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