ArticleBlood2022
Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.
Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 37 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Who cites it
37 citing papers in PubMed, 59 citations in OpenAlex.
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- Telomere-associated non-malignant pulmonary diseases: Pathogenic mechanisms and therapeutic strategies.Acta pharmaceutica Sinica. B · 2026Review
- Fission yeast RPA-TERT-Tpz1bioRxiv : the preprint server for biology · 2026Article
- Oxidative base damage to telomeres sensitizes cancer cells to ATR inhibition.Communications biology · 2026Article
- A homozygote mutation in RPA2 associated with bone marrow failure, immunodeficiency, and telomere biology disorder.European journal of human genetics : EJHG · 2026Article
- Clonal Signatures of Telomere Biology Disorders.Current hematologic malignancy reports · 2026Review
- Disrupted lipid homeostasis as a pathogenic mechanism in ABCA7-associated Alzheimer's disease risk.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Diagnosis and management of adult telomere biology disorders.Haematologica · 2026Review
- PUMA-induced apoptosis drives bone marrow failure and genomic instability in telomerase-deficient mice.Cell death and differentiation · 2026Article
- Genetic Familial Interstitial Lung Disease.Clinics in chest medicine · 2025Review
- Human RPA is an essential telomerase processivity factor for maintaining telomeres.Science (New York, N.Y.) · 2025Article
- Clinical and molecular features of immunodeficiency in patients with telomere biology disorders.Blood · 2025Article
- Telomere function and regulation from mouse models to human ageing and disease.Nature reviews. Molecular cell biology · 2025Review
- The canonical RPA complex interacts with Est3 to regulate yeast telomerase activity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Single-cell transcriptomic and m6A methylation analyses reveal platelet-mediated immune regulatory mechanisms in sepsis.Frontiers in immunology · 2025Article
- Hematological complications in solid organ transplant recipients with telomere biology disorders: a narrative review.Frontiers in immunology · 2025Review
- Human hnRNPA1 reorganizes telomere-bound replication protein A.Nucleic acids research · 2024Article
- Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment.Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie · 2024Review
- HeterozygousGenes & development · 2024Article
- Survival-Related Genes on Chromosomes 6 and 17 in Medulloblastoma.International journal of molecular sciences · 2024Article
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33 authors at 11 institutions in 5 countries.
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Abstract
Human telomere biology disorders (TBD)/short telomere syndromes (STS) are heterogeneous disorders caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify 3 germline heterozygous missense variants in the RPA1 gene in 4 unrelated probands presenting with short telomeres and varying clinical features of TBD/STS, including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, or skin manifestations. All variants cluster to DNA-binding domain A of RPA1 protein. RPA1 is a single-strand DNA-binding protein required for DNA replication and repair and involved in telomere maintenance. We showed that RPA1E240K and RPA1V227A proteins exhibit increased binding to single-strand and telomeric DNA, implying a gain in DNA-binding function, whereas RPA1T270A has binding properties similar to wild-type protein. To study the mutational effect in a cellular system, CRISPR/Cas9 was used to knock-in the RPA1E240K mutation into healthy inducible pluripotent stem cells. This resulted in severe telomere shortening and impaired hematopoietic differentiation. Furthermore, in patients with RPA1E240K, we discovered somatic genetic rescue in hematopoietic cells due to an acquired truncating cis RPA1 mutation or a uniparental isodisomy 17p with loss of mutant allele, coinciding with stabilized blood counts. Using single-cell sequencing, the 2 somatic genetic rescue events were proven to be independently acquired in hematopoietic stem cells. In summary, we describe the first human disease caused by germline RPA1 variants in individuals with TBD/STS.
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