Clinical and Molecular Heterogeneity of RTEL1 Deficiency

Frontiers in Immunology
Carsten SpeckmannMarcin W Wlodarski

Abstract

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 observ...Continue Reading

References

Sep 1, 1988·Acta paediatrica Scandinavica·S HreidarssonJ H Johannsson
Mar 1, 1970·Acta paediatrica Scandinavica·H M HoyeraalP J Moe
Sep 1, 1994·Leukemia & Lymphoma·I Dokal, L Luzzatto
May 10, 2002·Nucleic Acids Research·Richard M Cawthon
Apr 9, 2004·The EMBO Journal·Ulrich PannickeKlaus Schwarz
Sep 16, 2006·Molecular Cell·Jana RudolfMalcolm F White
Apr 5, 2007·Nature Protocols·Gabriela M BaerlocherPeter M Lansdorp
Jun 27, 2008·PLoS Biology·Stefanie C WolskiCaroline Kisker
Sep 12, 2008·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Victor AppayMario Roederer
Oct 30, 2008·Cell·Louise J BarberSimon J Boulton
Dec 17, 2009·The New England Journal of Medicine·Rodrigo T Calado, Neal S Young
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Nov 26, 2010·Nucleic Acids Research·Evert-Jan UringaSimon J Boulton
Feb 3, 2011·Pediatric Allergy and Immunology : Official Publication of the European Society of Pediatric Allergy and Immunology·S JyonouchiK E Sullivan
Feb 9, 2011·Proceedings of the National Academy of Sciences of the United States of America·Andrea Maul-PavicicStephan Ehl
Nov 15, 2011·The Journal of Allergy and Clinical Immunology·Fabien TouzotPatrick Revy
Dec 14, 2011·Hematology·Inderjeet Dokal
Dec 23, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Sebastian FuchsStephan Ehl
May 18, 2012·Molecular Biology of the Cell·Evert-Jan UringaPeter M Lansdorp
Mar 5, 2013·American Journal of Human Genetics·Amanda J WalneInderjeet Dokal
Jun 12, 2013·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Shahinaz M GadallaSharon A Savage
Aug 21, 2013·Proceedings of the National Academy of Sciences of the United States of America·Zhong DengYehuda Tzfati
May 30, 2015·The European Respiratory Journal·Caroline KannengiesserBruno Crestani
May 31, 2015·The Journal of Allergy and Clinical Immunology·Suheir HannaAmos Etzioni
Apr 30, 2016·Pediatric Blood & Cancer·Kunihiko MoriyaShigeo Kure

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Citations

Mar 10, 2018·Nucleic Acids Research·Rosa M PorrecaArturo Londoño-Vallejo
Jul 4, 2019·American Journal of Respiratory and Critical Care Medicine·Brett LeyPaul J Wolters
Jan 4, 2020·Journal of Pediatric Gastroenterology and Nutrition·Judith R KelsenAndrew B Grossman
Jul 28, 2020·Journal of Clinical Immunology·Alma ZivDror S Shouval
Jul 8, 2020·International Journal of Molecular Sciences·Valentino BezzerriMarco Cipolli
Jan 23, 2021·International Journal of Molecular Sciences·Megan Schmit, Anja-Katrin Bielinsky
Mar 14, 2021·Nature Communications·Ryan M BaxleyAnja-Katrin Bielinsky

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Methods Mentioned

BETA
FCS
flow cytometry
Exome Sequencing
Genotyping
PCR
biopsy
Chromosomal aberrations

Clinical Trials Mentioned

NCT00047268
NCT00662090

Software Mentioned

- Browser
CADD
Molsoft
PLINK
MPLUS AV
SIFT
Genome Analysis Toolkit
ICM
Affymetrix ® Genotyping
TASSER

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