Speckmann, Carsten ORCID: 0000-0002-6217-1556, Sahoo, Sushree Sangita, Rizzi, Marta, Hirabayashi, Shinsuke, Karow, Axel, Serwas, Nina Kathrin, Hoemberg, Marc, Damatova, Natalja, Schindler, Detlev, Vannier, Jean-Baptiste, Boulton, Simon J., Pannicke, Ulrich, Goehring, Gudrun, Thomay, Kathrin, Verdu-Amoros, J. J., Hauch, Holger, Woessmann, Wilhelm, Escherich, Gabriele, Laack, Eckart, Rindle, Liliana, Seidl, Maximilian, Rensing-Ehl, Anne, Lausch, Ekkehart, Jandrasits, Christine ORCID: 0000-0003-1357-4401, Strahm, Brigitte, Schwarz, Klaus, Ehl, Stephan R., Niemeyer, Charlotte, Boztug, Kaan ORCID: 0000-0001-8387-9185 and Wlodarski, Marcin W. (2017). Clinical and Molecular Heterogeneity of RTEL1 Deficiency. Front. Immunol., 8. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-3224

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Speckmann, CarstenUNSPECIFIEDorcid.org/0000-0002-6217-1556UNSPECIFIED
Sahoo, Sushree SangitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rizzi, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hirabayashi, ShinsukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karow, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serwas, Nina KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoemberg, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Damatova, NataljaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schindler, DetlevUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vannier, Jean-BaptisteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boulton, Simon J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pannicke, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goehring, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomay, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verdu-Amoros, J. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauch, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Woessmann, WilhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Escherich, GabrieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laack, EckartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rindle, LilianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seidl, MaximilianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rensing-Ehl, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lausch, EkkehartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jandrasits, ChristineUNSPECIFIEDorcid.org/0000-0003-1357-4401UNSPECIFIED
Strahm, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarz, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ehl, Stephan R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niemeyer, CharlotteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boztug, KaanUNSPECIFIEDorcid.org/0000-0001-8387-9185UNSPECIFIED
Wlodarski, Marcin W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-232773
DOI: 10.3389/fimmu.2017.00449
Journal or Publication Title: Front. Immunol.
Volume: 8
Date: 2017
Publisher: FRONTIERS MEDIA SA
Place of Publication: LAUSANNE
ISSN: 1664-3224
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HOYERAAL-HREIDARSSON SYNDROME; FAMILIAL PULMONARY-FIBROSIS; DNA-SEQUENCING DATA; DYSKERATOSIS-CONGENITA; COMBINED IMMUNODEFICIENCY; HOMOLOGOUS RECOMBINATION; TELOMERE MAINTENANCE; GENETIC FEATURES; MUTATIONS; HELICASEMultiple languages
ImmunologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23277

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