دورية أكاديمية
Clinical and Molecular Heterogeneity of RTEL1 Deficiency.
| العنوان: | Clinical and Molecular Heterogeneity of RTEL1 Deficiency. |
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| المؤلفون: | Speckmann C; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Sahoo SS; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany., Rizzi M; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Department of Rheumatology and Clinical Immunology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Hirabayashi S; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Karow A; Department of Paediatrics, Univeristy of Bern, Bern, Switzerland., Serwas NK; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Hoemberg M; Department of Pediatric Hematology and Oncology, Children's Hospital, University of Cologne, Cologne, Germany., Damatova N; Department of Medical Genetics, Biozentrum, University of Wuerzburg, Wuerzburg, Germany., Schindler D; Department of Medical Genetics, Biozentrum, University of Wuerzburg, Wuerzburg, Germany., Vannier JB; Telomere Replication and Stability Group, MRC London Institute of Medical Sciences (LMS), London, UK., Boulton SJ; Telomere Replication and Stability Group, MRC London Institute of Medical Sciences (LMS), London, UK., Pannicke U; Institute for Transfusion Medicine, Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, University Ulm, Ulm, Germany., Göhring G; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Thomay K; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Verdu-Amoros JJ; Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany., Hauch H; Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany., Woessmann W; Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany., Escherich G; Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Laack E; Hemato-Oncology Clinic Hamburg, Hamburg, Germany., Rindle L; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Seidl M; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Faculty of Medicine, Institute of Pathology, Medical Center, University of Freiburg, Freiburg, Germany., Rensing-Ehl A; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Lausch E; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Jandrasits C; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Strahm B; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Schwarz K; Institute for Transfusion Medicine, Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg - Hessen, University Ulm, Ulm, Germany., Ehl SR; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Niemeyer C; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK), Freiburg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Boztug K; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.; St. Anna Kinderspital and Children's Cancer Research Instutute, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria., Wlodarski MW; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK), Freiburg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany. |
| المصدر: | Frontiers in immunology [Front Immunol] 2017 May 01; Vol. 8, pp. 449. Date of Electronic Publication: 2017 May 01 (Print Publication: 2017). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Print ISSN: 1664-3224 (Print) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: [Lausanne : Frontiers Research Foundation] |
| مستخلص: | Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34 + cells failed to expand in vitro , B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy negatively impacts on the course and onset of other DC-related symptoms remains open at present. Early-onset lung disease occurred in one of our patients after HSCT. In conclusion, RTEL deficiency can show a heterogeneous clinical picture ranging from mild hypocellular BMF with B/NK cell lymphopenia to early-onset, very severe, and rapidly progressing cellular deficiency. |
| التعليقات: | Erratum in: Front Immunol. 2017 Oct 02;8:1250. (PMID: 28989339) |
| References: | Cell. 2008 Oct 17;135(2):261-71. (PMID: 18957201) J Allergy Clin Immunol. 2012 Feb;129(2):473-82, 482.e1-3. (PMID: 22078571) Eur Respir J. 2015 Aug;46(2):474-85. (PMID: 26022962) Acta Paediatr Scand. 1970 Mar;59(2):185-91. (PMID: 5442429) Blood. 2003 Apr 1;101(7):2711-20. (PMID: 12433688) Nucleic Acids Res. 2011 Mar;39(5):1647-55. (PMID: 21097466) Pediatr Allergy Immunol. 2011 May;22(3):313-9. (PMID: 21284747) Pediatr Blood Cancer. 2016 Sep;63(9):1683-4. (PMID: 27128385) Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3324-9. (PMID: 21300876) Hum Mol Genet. 2013 Aug 15;22(16):3239-49. (PMID: 23591994) Cell. 2012 May 11;149(4):795-806. (PMID: 22579284) Leuk Lymphoma. 1994 Sep;15(1-2):1-7. (PMID: 7858487) Proteins. 2014 Jun;82(6):897-903. (PMID: 24130156) N Engl J Med. 2009 Dec 10;361(24):2353-65. (PMID: 20007561) Nat Genet. 2015 May;47(5):512-7. (PMID: 25848748) Genome Res. 2010 Sep;20(9):1297-303. (PMID: 20644199) Hum Mutat. 2016 May;37(5):469-72. (PMID: 26847928) Haematologica. 2016 Nov;101(11):1343-1350. (PMID: 27418648) Haematologica. 2013 Mar;98(3):473-8. (PMID: 22801960) J Immunol. 2012 Feb 1;188(3):1523-33. (PMID: 22190180) Nat Methods. 2010 Apr;7(4):248-9. (PMID: 20354512) Biol Blood Marrow Transplant. 2013 Aug;19(8):1238-43. (PMID: 23751955) Nat Protoc. 2010 Apr;5(4):725-38. (PMID: 20360767) Cell. 2004 Jun 25;117(7):873-86. (PMID: 15210109) Acta Paediatr Scand. 1988 Sep;77(5):773-5. (PMID: 3201986) Int J Hematol. 2015 Nov;102(5):544-52. (PMID: 26329388) Hum Genet. 2013 Apr;132(4):473-80. (PMID: 23329068) Nature. 2016 Aug 17;536(7616):285-91. (PMID: 27535533) Nat Genet. 2011 May;43(5):491-8. (PMID: 21478889) Am J Cancer Res. 2015 Jun 15;5(7):2294-300. (PMID: 26328260) Lancet. 1998 Jan 17;351(9097):178-81. (PMID: 9449873) Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):E3408-16. (PMID: 23959892) Mol Biol Cell. 2012 Jul;23(14):2782-92. (PMID: 22593209) Eur Respir J. 2017 Jan 25;49(1):null. (PMID: 27824607) PLoS Biol. 2008 Jun 24;6(6):e149. (PMID: 18578568) EMBO J. 2004 May 5;23(9):1987-97. (PMID: 15071507) J Allergy Clin Immunol. 2015 Oct;136(4):1113-4. (PMID: 26025130) Nat Genet. 2014 Mar;46(3):310-5. (PMID: 24487276) Am J Hum Genet. 2013 Mar 7;92(3):448-53. (PMID: 23453664) Haematologica. 2012 Mar;97(3):353-9. (PMID: 22058220) Hematology Am Soc Hematol Educ Program. 2007;:29-39. (PMID: 18024606) Hematology Am Soc Hematol Educ Program. 2011;2011:480-6. (PMID: 22160078) Am J Hum Genet. 2007 Sep;81(3):559-75. (PMID: 17701901) Nat Protoc. 2009;4(7):1073-81. (PMID: 19561590) Bone Marrow Transplant. 2016 May;51(5):753-4. (PMID: 26808564) Arch Intern Med. 1984 Feb;144(2):397-9. (PMID: 6607716) Nat Protoc. 2006;1(5):2365-76. (PMID: 17406480) Science. 2013 Oct 11;342(6155):239-42. (PMID: 24115439) Blood. 2008 Nov 15;112(10):4090-7. (PMID: 18728247) Mol Cell. 2006 Sep 15;23(6):801-8. (PMID: 16973432) Eur Respir J. 2016 Dec;48(6):1710-1720. (PMID: 27540018) PLoS Genet. 2013 Aug;9(8):e1003695. (PMID: 24009516) Nucleic Acids Res. 2002 May 15;30(10):e47. (PMID: 12000852) Cytometry A. 2008 Nov;73(11):975-83. (PMID: 18785267) Blood. 2012 Mar 15;119(11):e96-9. (PMID: 22238327) |
| معلومات مُعتمدة: | 11581 United Kingdom CRUK_ Cancer Research UK; Y 595 Austria FWF_ Austrian Science Fund FWF |
| فهرسة مساهمة: | Keywords: RTEL1; bone marrow failure; dyskeratosis congenita; immunodeficiency; lymphopenia |
| تواريخ الأحداث: | Date Created: 20170517 Latest Revision: 20240214 |
| رمز التحديث: | 20240214 |
| مُعرف محوري في PubMed: | PMC5410638 |
| DOI: | 10.3389/fimmu.2017.00449 |
| PMID: | 28507545 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2017.00449 |