Journal
FRONTIERS IN IMMUNOLOGY
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2017.00449
Keywords
RTEL1; dyskeratosis congenita; bone marrow failure; immunodeficiency; lymphopenia
Categories
Funding
- Deutsche Krebshilfe Max Eder Grant [109005]
- BMBF [01GM1301]
- German Federal Ministry of Education and Research (DKTK German cancer consortium)
- German Federal Ministry of Education and Research (molecular diagnostics of pediatric malignancies)
- Austrian Science Fund (FWF): START Program Project [Y595-B13]
- Jeffrey Modell Foundation Translational Research Program grant
- ERC under the European Union's Seventh Framework Program (FP7)/ERC [310857]
- ELITE program (Baden Wurttemberg Stiftung)
- German Federal Ministry of Education and Research [BMBF 01 EO 0803, BMBF 01GM1517C]
- Cancer Research UK
- ERC Advanced Investigator Grant (RecMitMei)
- Royal Society Wolfson Research Merit Award
- ERC
- European Research Council (ERC) [310857] Funding Source: European Research Council (ERC)
- Cancer Research UK [11581] Funding Source: researchfish
- The Francis Crick Institute [10627, 742437-TelMetab, 703228 - RTEL1] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10048] Funding Source: researchfish
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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.
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