Page 47 - Haematologica June

Red Cell Biology & its Disorders
Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia
Marcin W. Wlodarski,1,2 Lydie Da Costa,3,4,5,6 Marie-Françoise O'Donohue,7 Marc Gastou,3,4,8 Narjesse Karboul,3,5 Nathalie Montel-Lehry,7 Ina Hainmann,1 Dominika Danda,1,9 Amina Szvetnik,1 Victor Pastor,1,10 Nahuel Paolini,11 Franca M. di Summa,11 Hannah Tamary,12,13 Abed Abu Quider,14
Anna Aspesi,15 Riekelt H. Houtkooper,16 Thierry Leblanc,17 Charlotte M. Niemeyer,1,2 Pierre-Emmanuel Gleizes7 and Alyson W. MacInnes16
1Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany; 2German Cancer Consortium (DKTK), Freiburg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany; 3University Paris VII Denis Diderot, Faculté de Médecine Xavier Bichat, Paris, France; 4Laboratory of Excellence for Red Cell, LABEX GR-Ex, Paris, France; 5Inserm Unit 1149, CRI, Paris, France; 6Hematology Laboratory, Robert Debré Hospital, Paris, France; 7LBME, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France; 8UMR1170, Gustave Roussy, Villejuif, France; 9Department of Tumor Pathology, Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Poland; 10Faculty of Biology, University of Freiburg, Germany; 11Department of Hematopoiesis, Sanquin and Landsteiner Laboratory, AMC/UvA, CX Amsterdam, the Netherlands; 12Hematology Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; 13Sackler School of Medicine, Tel Aviv University, Israel; 14Pediatric Hematology/Oncology Department, Soroka Medical Center, Faculty of Medicine, Ben- Gurion University, Beer Sheva, Israel; 15Dipartimento di Scienze della Salute, Università del Piemonte Orientale, Novara, Italy; 16Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands and 17Pediatric Hematology Service, Robert-Debré Hospital and EA-3518, Université Paris Diderot - Institut Universitaire d'Hématologie, Paris, France
ABSTRACT
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 diag- nosed with DBA. Although point mutations have not been previously reported for RPL15, we identified 4 individuals with truncating muta- tions 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 muta- tion 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 poten- tial mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA pro- cessing 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 muta- tions in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission.
Introduction
Diamond-Blackfan anemia (DBA) (OMIM# 105650) is an inherited bone mar- row failure disorder that typically manifests in children under the age of one year. While the central phenotype is pure red cell aplasia, developmental delay and a
Ferrata Storti Foundation
Haematologica 2018 Volume 103(6):949-958
Correspondence:
marcin.wlodarski@uniklinik-freiburg.de
Received: August 4, 2017. Accepted: March 6, 2018. Pre-published: March 29, 2018.
doi:10.3324/haematol.2017.177980
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/949
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