Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia.

Autor:	Wlodarski MW; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany.; German Cancer Consortium (DKTK), Freiburg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany., Da Costa L; University Paris VII Denis Diderot, Faculté de Médecine Xavier Bichat, Paris, France.; Laboratory of Excellence for Red Cell, LABEX GR-Ex, Paris, France.; Inserm Unit 1149, CRI, Paris, France.; Hematology Laboratory, Robert Debré Hospital, Paris, France., O'Donohue MF; LBME, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France., Gastou M; University Paris VII Denis Diderot, Faculté de Médecine Xavier Bichat, Paris, France.; Laboratory of Excellence for Red Cell, LABEX GR-Ex, Paris, France.; UMR1170, Gustave Roussy, Villejuif, France., Karboul N; University Paris VII Denis Diderot, Faculté de Médecine Xavier Bichat, Paris, France.; Inserm Unit 1149, CRI, Paris, France., Montel-Lehry N; LBME, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France., Hainmann I; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany., Danda D; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany.; Department of Tumor Pathology, Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Poland., Szvetnik A; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany., Pastor V; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany.; Faculty of Biology, University of Freiburg, Germany., Paolini N; Department of Hematopoiesis, Sanquin and Landsteiner Laboratory, AMC/UvA, CX Amsterdam, the Netherlands., di Summa FM; Department of Hematopoiesis, Sanquin and Landsteiner Laboratory, AMC/UvA, CX Amsterdam, the Netherlands., Tamary H; Hematology Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.; Sackler School of Medicine, Tel Aviv University, Israel., Quider AA; Pediatric Hematology/Oncology Department, Soroka Medical Center, Faculty of Medicine, Ben-Gurion University, Beer Sheva, Israel., Aspesi A; Dipartimento di Scienze della Salute, Università del Piemonte Orientale, Novara, Italy., Houtkooper RH; Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands., Leblanc T; Pediatric Hematology Service, Robert-Debré Hospital and EA-3518, Université Paris Diderot - Institut Universitaire d'Hématologie, Paris, France., Niemeyer CM; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany.; German Cancer Consortium (DKTK), Freiburg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany., Gleizes PE; LBME, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France., MacInnes AW; Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands marcin.wlodarski@uniklinik-freiburg.de.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2018 Jun; Vol. 103 (6), pp. 949-958. Date of Electronic Publication: 2018 Mar 29.
DOI:	10.3324/haematol.2017.177980
Abstrakt:	Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure disorder linked predominantly to ribosomal protein gene mutations. Here the European DBA consortium reports novel mutations identified in the RPL15 gene in 6 unrelated individuals diagnosed with DBA. Although point mutations have not been previously reported for RPL15 , we identified 4 individuals with truncating mutations p.Tyr81* (in 3 of 4) and p.Gln29*, and 2 with missense variants p.Leu10Pro and p.Lys153Thr. Notably, 75% (3 of 4) of truncating mutation carriers manifested with severe hydrops fetalis and required intrauterine transfusions. Even more remarkable is the observation that the 3 carriers of p.Tyr81* mutation became treatment-independent between four and 16 months of life and maintained normal blood counts until their last follow up. Genetic reversion at the DNA level as a potential mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA processing defects, reduced 60S ribosomal subunit formation, and severe proliferation defects. Red cell culture assays of RPL15 -mutated primary erythroblast cells also showed a severe reduction in cell proliferation, delayed erythroid differentiation, elevated TP53 activity, and increased apoptosis. This study identifies a novel subgroup of DBA with mutations in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission. (Copyright © 2018 Ferrata Storti Foundation.)
Databáze:	MEDLINE
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