THE RIBOSOMAL BASIS OF DIAMOND-BLACKFAN ANEMIA: MUTATION AND DATABASE UPDATE

Ilenia Boria (1) , Emanuela Garelli (2) , Hanna T. Gazda (3, 4) , Anna Aspesi (1) , Paola Quarello (2) , Elisa Pavesi (1) , Daniela Ferrante (1) , Joerg J. Meerpohl (5) , Mutlu Kartal (5) , Lydie da Costa (6, 7, 8) , Alexis Proust (9) , Thierry Leblanc (6) , Maud Simansour (6) , Niklas Dahl (10) , Anne-Sophie Fröjmark (10) , Dagmar Pospisilova (11) , Radek Cmejla (12) , Alan H. Beggs (3, 4) , Mee Rie Sheen (3) , Michael Landowski (3) , Christopher Buros (3) , Catherine Clinton (3) , Lori Dobson (3) , Adrianna Vlachos (13, 14) , Eva Atsidaftos (13, 14) , Jeffrey M. Lipton (13, 14) , Steven Ellis (15) , Ugo Ramenghi (2) , Irma Dianzani (1)

1 Dept. Medical Sciences,
2 Dept. of Pediatrics,
3 Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research,
4 HMS - Harvard Medical School [Boston]
5 Pediatric Hematology & Oncology, Dept. of Pediatric and Adolescent Medicine,
6 AP-HP, Service d'Hématologie Biologique,
7 Hématopoïèse normale et pathologique
8 UPD7 - Université Paris Diderot - Paris 7
9 Hematology Laboratory,
10 Dept. of Genetics and Pathology, Section of Clinical Genetics, The Rudbeck laboratory,
11 Dept. of Pediatrics,
12 Dept. of Cell Physiology,
13 The Feinstein Institute for Medical Research,
14 Cohen Children's Medical Center of New York, Hofstra University School of Medicine,
15 University of Louisville,

Diamond-Blackfan Anemia (DBA) is characterized by a defect in erythroid progenitor differentation and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database.

Mots clés: Life Sciences

Ilenia Boria, Emanuela Garelli, Hanna T. Gazda, Anna Aspesi, Paola Quarello, et al.. THE RIBOSOMAL BASIS OF DIAMOND-BLACKFAN ANEMIA: MUTATION AND DATABASE UPDATE. Human Mutation, 2010, 31 (12), pp.1269. ⟨10.1002/humu.21383⟩. ⟨hal-00594911⟩