INSERM U362, Institut Gustave-Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif Cedex, Centre de référence des maladies génétiques de l’érythrocyte et de l’érythropoïèse, hôpital Bicêtre, 78 avenue du Général-Leclerc, 94275 Le Kremlin-Bicêtre Cedex, Service d’hématologie-oncologie pédiatrique, hôpital Saint-Louis, 1 rue Claude-Vellefaux, 75010 Paris
Diamond-Blackfan anemia (DBA), a rare constitutional erythroblastopenia, is a striking heterogeneous disorder as far as phenotypic expression, therapeutic response or genetic status are concerned. In the eighties, the creation of DBA patient international registries, the collaboration between international research teams, and the support of DBA patients and their families lead to a better understanding of the disease. The first gene was identified in 1999, and, unexpectedly, is coding for a ribosomal protein, the RPS19. However, rps19 gene mutations are only found in 25 % of DBA cases. A second locus has been identified on chromosome 8 and linkage analysis suggests that at least a 3
rd chromosome is involved in the disease. In apparently healthy family members, rps19 gene mutations, identical to those of the proband, can be observed, defining a silent phenotype. DBA pathophysiology remains ill defined and its relevance in erythropoiesis or morphogenesis is poorly understood. Animal models have been disappointing. The homozygous knock-out mice model is lethal while the heterozygous one is devoid of phenotypic expression. In fruit fly, a minute-like syndrome has been obtained after insertion of a P-element in rps19 gene, but it does not allow any analysis of hematopoiesis. Progress will be achieved when new insights in deciphering the DBA pathophysiology, in particular the role of RPS19 in erythropoiesis, will be obtained. The ribosomal biogenesis and assembly, and the place of RPS19 in this co-ordinated and complex process, is an important challenge to resolve. New therapeutics may then be produced and offered to the DBA patients.