Diamond-Blackfan anemia, ribosome and erythropoiesis

Abstract

Diamond-Blackfan anemia is a rare inherited bone marrow failure syndrome (5 to 7 cases/million live births) characterized by an are generative, usually macrocytic anemia with an absence or less than 5% of erythroid precursors (erythroblastopenia) in an otherwise normal bone marrow. The platelet and the white cell counts are usually normal but neutropenia, thrombopenia or thrombocytosis have been noted at diagnosis. In 40 to 50% of DBA patients, congenital abnormalities mostly in the cephalic area and in thumbs and upper limbs have been described. Recent analysis did show a phenotype/genotype correlation. Congenital erythroblastopenia of DBA is the first human disease identified to result from defects in ribosomal biogenesis. The first ribosomal gene involved in DBA, ribosomal protein (RP) gene S19 (RPS19 gene), was identified in 1999. Subsequently, mutations in 12 other RP genes out of a total of 78 RP genes have been identified in DBA. All RP gene mutations described to date are heterozygous and dominant inheritance has been documented in 40 to 45% of affected individuals. As RP mutations are yet to be identified in approximately 50% of DBA cases, it is likely that other yet to be identified genes involved in ribosomal biogenesis or other pathways may be responsible for DBA phenotype.

Cardiomyopathy Is Associated with Ribosomal Protein Gene Haplo-Insufficiency inDrosophila melanogaster

“…Human CRP and MRP genes have been established as candidates for causing human syndromes and diseases (Draptchinskaia et al 1999;Ruggero and Pandolfi 2003;O'brien et al 2005;Da Costa et al 2010;Freed et al 2010;Ito et al 2010;Narla and Ebert 2010). Diamond Blackfan anemia is associated with mutations in several haplo-insufficient CRP genes (Draptchinskaia et al 1999;Da Costa et al 2010;Ito et al 2010) and is characterized by congenital defects, including cardiac abnormalities (Ito et al 2010;Doherty et al 2010).…”

“…Diamond Blackfan anemia is associated with mutations in several haplo-insufficient CRP genes (Draptchinskaia et al 1999;Da Costa et al 2010;Ito et al 2010) and is characterized by congenital defects, including cardiac abnormalities (Ito et al 2010;Doherty et al 2010). Mutations in the gene encoding ribosomal protein RPS19 have been identified in approximately 25% of Diamond Blackfan anemia families and haplo-insufficiency of several other CRP genes have subsequently been found in affected patients (Da Costa et al 2010). Studies in transgenic mice expressing a mutated RPS19 gene suggest that one mechanism by which mutations in RPS19 can cause Diamond Blackfan anemia is by its effect as a dominant negative protein (Devlin et al 2010).…”

The Stomatological Complications of Diamond-Blackfan Anemia: A Case Report

“…15 Some patients present with congenital anomalies concomitant to DBA, such as craniofacial, cardiac, genitourinary, and upper limb inborn deformities. 1,2,[4][5][6][7][16][17][18][19] Low birth weight and growth retardation are also reported. With no specific role described so far, 1,7,8 ribosomal protein S19 (RP S19) was the first mutated gene to be linked to DBA.…”

“…9,13,14 Thrombocytopenia and neutropenia may occur, 9,13 and reticulocytopenia, normal macrocytosis, and cellularity of the bone marrow should also be considered besides reduction of erythroid progenitors. 1,15,16,24 Corticosteroid therapy is the main treatment approach to DBA, since a positive response is observed in most cases, 1,5,6 and the disease remains controlled in others for a considerable length of time. 7 Nevertheless, approximately 50% of patients discontinue the treatment due to the loss of clinical efficacy or to secondary effects.…”

“…1,2,23 Research has described the curative role of hematopoietic stem cell transplantation (HSCT) in DBA. 1,6,16,19,23,25 The clinical evolution of DBA patients is unpredictable, and complications are usually severe, most of which are associated with treatment due to the chronic use of corticosteroids, increased iron levels, infections, and side effects associated with transplantation. 16,18 In addition, DBA patients are at higher risk of acquiring malignant diseases, solid tumors (bone, breast, and digestive tract cancers), and hematological neoplasias.…”