A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

Takai, Hiroyuki; Jenkinson, Emma; Kabir, Shaheen; Babul‐Hirji, Riyana; Najm-Tehrani, Nasrin; Chitayat, David; Crow, Yanick J.; Lange, Titia de

doi:10.1101/gad.276873.115

Cited by 88 publications

(94 citation statements)

References 72 publications

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“…Telomeric singlestranded 39 overhang was measured, as previously described. 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%

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: Functional Assaysmentioning

confidence: 99%

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

et al. 2018

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“…75–80 In CLL, Pot1 is one of the most frequently mutated genes with 3.5% of CLL cases containing somatic mutations in Pot1. Strikingly, most of the disease-associated point mutations occur at residues contacting DNA in the crystal structure of hPOT1-DBD (Figure 3B).…”

Section: Shelterin and The Pot1 Proteinmentioning

confidence: 99%

“…65 Conversely, some of these mutations lead to telomere shortening, currently ascribed to a loss of interaction with another ssDNA binding complex of hCTC1-hSTN1-hTEN1 and suppression of appropriate lagging strand synthesis. 80 This differential impact speaks to the complexity of processing at the telomere and the myriad roles hPOT1 plays.…”

Section: Shelterin and The Pot1 Proteinmentioning

confidence: 99%

Tying up the Ends: Plasticity in the Recognition of Single-Stranded DNA at Telomeres

et al. 2016

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Telomeres terminate nearly exclusively in ssDNA overhangs comprised of the G-rich 3′ end. This overhang varies widely in length from species to species, ranging from just a few bases to several hundred nucleotides. These overhangs are not merely a remnant of DNA replication, but rather are the result of complex further processing. Proper management of the telomeric overhang is required both to deter the action of the DNA-damage machinery and to present the ends properly to the replicative enzyme telomerase. This Current Topic review addresses the biochemical and structural features used by the proteins that manage these variable telomeric overhangs. The Pot1 protein tightly binds the single-stranded overhang, preventing DNA damage sensors from binding. Pot1 also orchestrates the access of telomerase to that same substrate. The remarkable plasticity of the binding interface exhibited by the S. pombe Pot1 provides mechanistic insight into how these roles may be accomplished, and disease-associated mutations clustered around the DNA-binding interface in the hPOT1 highlight the importance of this function. The budding yeast Cdc13-Stn1-Ten1, a telomeric RPA complex closely associated with telomere function, also interacts with ssDNA in a fashion that allows degenerate sequences to be recognized. A related human complex composed of hCTC1-hSTN1-hTEN1 has recently emerged with links to both telomere maintenance and general DNA replication and also exhibits mutations associated with telomere pathologies. Overall, these sequence-specific ssDNA binders exhibit a range of recognition properties that allow them to perform their unique biological functions.

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“…Although the phenotype of the exclusively neurological disease LCC is highly distinctive, it is not pathognomonic, as a remarkably similar radiological association is seen in the context of the multisystem disorder Coats plus. Coats plus is caused by mutations in CTC1 (37) and STN1 (38), both components of the conserved heterotrimeric telomeric capping complex, and in the telomeric protein POT1 (39). Interestingly then, an unbiased enChip-RNAseq approach identified U8 as a telomere associated RNA (40).…”

Section: Discussionmentioning

confidence: 99%

Novel intramolecular base-pairing of the U8 snoRNA underlies a Mendelian form of cerebral small vessel disease

Badrock

Uggenti

Wacheul

et al. 2019

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How mutations in the non-coding U8 snoRNA cause the neurological disorder leukoencephalopathy with calcification and cysts (LCC) is poorly understood. We report the first vertebrate mutant U8 animal model for interrogating LCC-associated pathology. Mutant U8 zebrafish exhibit defective central nervous system development and ribosomal RNA (rRNA) biogenesis, with tp53 activation which monitors ribosome biogenesis. Importantly, LCC patient fibroblasts demonstrate rRNA processing defects. Human precursor-U8 (pre-U8) containing a 3´ extension rescued mutant U8 zebrafish, indicating conserved biological function. Analysis of LCCassociated U8 alleles in zebrafish revealed that one null and one hypomorphic, but still functional, allele combine to cause LCC. Mutations involving any one of seven nucleotides within the human pre-U8 3´ extension, or 5´ region of U8, alter processing of pre-U8, and identify a novel basepairing interaction between the 5´ end and 3´ extension of human pre-U8. Variants in these seven nucleotides, one of which is present on a single allele in almost all patients, act as hypomorphic mutations. Given that biallelic null U8 alleles are likely incompatible with human development, identification of hypomorphic mutations mediating viable embryogenesis furthers understanding of LCC molecular pathology and cerebral vascular homeostasis.

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A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

Cited by 88 publications

References 72 publications

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

Tying up the Ends: Plasticity in the Recognition of Single-Stranded DNA at Telomeres

Novel intramolecular base-pairing of the U8 snoRNA underlies a Mendelian form of cerebral small vessel disease

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