TY - JOUR AU - Marcin W. Wlodarski, AU - Lydie Da Costa, AU - Marie-Françoise O’Donohue, AU - Marc Gastou, AU - Narjesse Karboul, AU - Nathalie Montel-Lehry, AU - Ina Hainmann, AU - Dominika Danda, AU - Amina Szvetnik, AU - Victor Pastor, AU - Nahuel Paolini, AU - Franca M. di Summa, AU - Hannah Tamary, AU - Abed Abu Quider, AU - Anna Aspesi, AU - Riekelt H. Houtkooper, AU - Thierry Leblanc, AU - Charlotte M. Niemeyer, AU - Pierre-Emmanuel Gleizes, AU - Alyson W. MacInnes, PY - 2018/06/03 Y2 - 2024/03/29 TI - Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia JF - Haematologica JA - haematol VL - 103 IS - 6 SE - Articles DO - 10.3324/haematol.2017.177980 UR - https://haematologica.org/article/view/8490 SP - 949-958 AB - 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. ER -