TY - JOUR
T1 - Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in diamond-blackfan anemia
AU - Wlodarski, Marcin W.
AU - da Costa, Lydie
AU - O'donohue, Marie-Françoise
AU - Gastou, Marc
AU - Karboul, Narjesse
AU - Montel-Lehry, Nathalie
AU - Hainmann, Ina
AU - Danda, Dominika
AU - Szvetnik, Amina
AU - Pastor, Victor
AU - Paolini, Nahuel
AU - di Summa, Franca M.
AU - Tamary, Hannah
AU - Quider, Abed Abu
AU - Aspesi, Anna
AU - Houtkooper, Riekelt H.
AU - Leblanc, Thierry
AU - Niemeyer, Charlotte M.
AU - Gleizes, Pierre-Emmanuel
AU - Macinnes, Alyson W.
PY - 2018
Y1 - 2018
N2 - 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.
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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85048056597&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29599205
U2 - https://doi.org/10.3324/haematol.2017.177980
DO - https://doi.org/10.3324/haematol.2017.177980
M3 - Article
C2 - 29599205
SN - 0390-6078
VL - 103
SP - 949
EP - 958
JO - Haematologica
JF - Haematologica
IS - 6
ER -