4th Palermo Conference on INNOVATIVE THERAPIES FOR LYMPHOID MALIGNANCIES
Published online 22 September 2009
Haematologica, Vol 95, Issue 2, 206-213 doi:10.3324/haematol.2009.011783
Copyright © 2010 by Ferrata Storti Foundation
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Bone Marrow Failure

Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations

Paola Quarello1, Emanuela Garelli1, Adriana Carando1, Alfredo Brusco2, Roberto Calabrese1, Carlo Dufour3, Daniela Longoni4, Aldo Misuraca5, Luciana Vinti6, Anna Aspesi7, Laura Biondini8, Fabrizio Loreni8, Irma Dianzani7, Ugo Ramenghi1

1 Hematology Unit, Pediatric Department, University of Torino
2 Department of Genetics, Biology and Biochemistry, University of Torino
3 Pediatric Hematology, IRCCS Gaslini, Genova
4 Pediatric Department, University of Milano Bicocca, Monza
5 Onco-Hematology, Pausillipon Hospital, Napoli
6 Pediatric Oncology and Hematology, IRCCS San Matteo, Pavia
7 Department of Medical Sciences, University of Eastern Piedmont, Novara
8 Department of Biology, University ‘Tor Vergata’, Roma, Italy

Correspondence: Ugo Ramenghi, MD, Associate Professor of Pediatrics, Hematology Unit, Pediatric Department, University of Torino Piazza Polonia 94, 10126 Torino, Italy. E-mail: ugo.ramenghi{at}unito.it

Background: Diamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients.

Design and Methods: In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations.

Results: About 20% of the patients screened had mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations.

Conclusions: Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations.

Key words: red cells, bone marrow failure, anemia, DBA, ribosomal proteins.