Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

Touzot, Fabien; Kermasson, Laëtitia; Jullien, Laurent; Moshous, Despina; Ménard, Christelle; İkincioğulları, Aydan; Doğu, Figen; Sarı, Sinan; Giacobbi-Milet, Vannina; Etzioni, Amos; Soulier, Jean; Londoño-Vallejo, Arturo; Fischer, Alain; Callebaut, Isabelle; Villartay, Jean-Pierre de; Leblanc, Thierry; Kannengiesser, Caroline; Revy, Patrick

doi:10.1182/bloodadvances.2016001313

Cited by 24 publications

(40 citation statements)

References 37 publications

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“…The t-circle assay is used as a marker to identify RTEL1 deficient cells; however, as is seen in our results, other studies did not identify any accumulation of t-circles in patients' cells. 9,10 The interpretation of functional assays is still limited to what is known about the role of RTEL1 dysfunction in cell biology. Here, we describe RTEL1 as a modulator of TRF2 expression in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…22,23 RNA and DNA were extracted from NIH patients' PB for gene expression analysis and telomere circle (TC) assay, respectively, as described with minor modifications. 5,10,24 Signaling pathways related to DNA damage, apoptosis, and senescence or telomere and telomerase maintenance were evaluated in patient samples by polymerase chain reaction (PCR) array.…”

Section: Functional Assaysmentioning

confidence: 99%

“…4,5 Biallelic mutations in RTEL1, either in homozygosity or compound heterozygosity, provoke extreme telomere erosion and severe phenotype, clinically manifested as dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson (HH) syndrome in early childhood. [6][7][8][9][10] TERT or TERC haploinsufficiency due to heterozygous mutations also results in telomere shortening and is identified in up to 10% of patients with aplastic anemia (AA) or myeloid malignancies. [11][12][13] Heterozygous RTEL1 mutations have been reported in idiopathic pulmonary fibrosis (IPF) 14,15 but are not common in hematologic disorders.…”

Section: Introductionmentioning

confidence: 99%

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Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

et al. 2018

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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.Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n 5 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n 5 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 39 telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants.Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

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Section: Discussionmentioning

confidence: 99%

Section: Functional Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

et al. 2018

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“…At the cellular level, these diseases are associated with very short and heterogeneous telomeres, genomic instability, and sensitivity to clastogens, consistent with the role of RTEL1 in preserving genome integrity (Ballew et al, 2013a;Faure et al, 2013). Some disease-causing RTEL1 alleles exhibit autosomal dominant behavior, suggesting that the protein may function in a dimeric or multimeric assembly (Ballew et al, 2013b;Borie et al, 2019;Newton et al, 2016;Touzot et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

RTEL1 Influences the Abundance and Localization of TERRA RNA

Ghisays

Garzia

Wang

et al. 2020

Preprint

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Telomere repeat containing RNAs (TERRAs) are a family of long noncoding RNAs transcribed from the sub-telomeric regions of eukaryotic chromosomes. TERRA transcripts can form R-loops at chromosome ends; however the importance of these structures or the regulation of TERRA expression and retention in telomeric R-loops remain unclear. Here, we show that the RTEL1 (Regulator of Telomere Length 1) helicase influences the abundance and localization of TERRA in human cells. Depletion of RTEL1 leads to increased levels of TERRA RNA while reducing TERRA-containing R loops at telomeres. In vitro, RTEL1 shows a strong preference for binding G-quadruplex structures which form in TERRA. This binding is mediated by the C-terminal region of RTEL1, and is independent of the RTEL1 helicase domain. RTEL1binding to TERRA appears to be essential for cell viability, underscoring the importance of this function. Degradation of TERRA containing R-loops by overexpression of RNAse H1 partially recapitulates the increased TERRA levels and telomeric instability associated with RTEL1 deficiency. Collectively, these data suggest that regulation of TERRA at the telomeres is a key function of the RTEL1 helicase, and that loss of that function may contribute to the disease phenotypes of patients with RTEL1 mutations. 2017). Despite this broad distribution of binding sites, the most prominent role of TERRA is at the telomere. Depletion of TERRA leads to myriad indices of telomere dysfunction such as the loss of telomeric DNA, the formation of telomere damage associated foci (TIFs) (Takai et al., 2003), and telomere driven chromosome aberrations. Notably, TERRA interacts with, and appears to antagonize the functions of the chromatin remodeler ATRX, which plays a key role in modulating telomeric chromatin structure (Chu et al., 2017; Eid et al., 2015;Nguyen et al., 2017).Due to its G-rich sequence, TERRA can form stable, four-stranded structures known as G-quadruplexes in vitro (Bao et al., 2017; Biffi et al., 2012;Sen and Gilbert, 1988). G-quadruplex structures can form in both G-rich DNA and RNA sequences in vitro under physiological conditions, and are likely to constitute barriers to protein translocation during DNA replication, transcription, and mRNA translation if present in cells (Hansel-Hertsch et al., 2017). There are dedicated protein machineries with the capacity to unfold G-quadruplex structures in mammalian cells (Guo and Bartel, 2016). However, it is not clear whether TERRA forms G-quadruplex structures in vivo and if so, whether those structures are biologically relevant.Here we present evidence that RTEL1 influences the levels and localization of TERRA via direct physical interaction. We identified an RNA binding domain in the RTEL1 C-terminus that exhibits a strong preference for G-quadruplex folded TERRA RNA over unfolded RNA. RTEL1 deficiency causes a dramatic

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“…Hoyeraal-Hreidarsson (HH) syndrome in early childhood (Ballew et al, 2013;Deng et al, 2013;Le Guen et al, 2013;Walne et al, 2013;Touzot and Kermasson, 2016). TERT or TERC haploinsufficiency due to heterozygous mutations also results in telomere shortening and is associated with less severe phenotype and is identified in up to 10% of patients with AA or myeloid malignancies (Yamaguchi et al, 2003;Yamaguchi et al, 2005;Calado, Regal, Hills, et al, 2009).…”

Section: Bone Marrow Failure Syndromesmentioning

confidence: 99%

Identificação de moduladores genéticos em pacientes com anemia aplástica por sequenciamento de nova geração

Rodrigues¹

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Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

Cited by 24 publications

References 37 publications

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

RTEL1 Influences the Abundance and Localization of TERRA RNA

Identificação de moduladores genéticos em pacientes com anemia aplástica por sequenciamento de nova geração

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