Clinical utility gene card for: Diamond – Blackfan Anemia – update 2013

Vlachos, Adrianna; Dahl, Niklas; Dianzani, Irma; Lipton, Jeffrey M.

doi:10.1038/ejhg.2013.34

Cited by 26 publications

(21 citation statements)

References 23 publications

(20 reference statements)

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“…12 Mutations in ribosomal genes account for 60% to 70% of DBA cases. Of these ribosomal gene mutations, around 20% involve large deletions that require analysis of copy number variation for detection.…”

Section: Diamond-blackfan Anemia: Geneticsmentioning

confidence: 99%

Marrow failure: a window into ribosome biology

Ruggero

Shimamura

2014

Blood

107

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Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita are inherited syndromes characterized by marrow failure, congenital anomalies, and cancer predisposition. Genetic and molecular studies have uncovered distinct abnormalities in ribosome biogenesis underlying each of these 3 disorders. How defects in ribosomes, the essential organelles required for protein biosynthesis in all cells, cause tissue-specific abnormalities in human disease remains a question of fundamental scientific and medical importance. Here we review the overlapping and distinct clinical features of these 3 syndromes and discuss current knowledge regarding the ribosomal pathways disrupted in each of these disorders. We also explore the increasing complexity of ribosome biology and how this informs our understanding of developmental biology and human disease.

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Section: Diamond-blackfan Anemia: Geneticsmentioning

confidence: 99%

Marrow failure: a window into ribosome biology

Ruggero

Shimamura

2014

Blood

107

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“…1,2 Approximately 70% of DBA patients have mutations in ribosomal proteins, most frequently in RPS19. 3 Previous studies in human CD34…”

Section: Introductionmentioning

confidence: 99%

TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19-deficient hematopoietic progenitors

Бибикова

Youn

Danilova

et al. 2014

Blood

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Key Points• GATA1 is downregulated in RPS19-deficient cells and zebrafish through upregulation of p53, TNF-a, and p38 MAPK.• Treatment of rps19-deficient zebrafish with the TNF-a inhibitor etanercept rescues their erythroid and developmental defects.Diamond-Blackfan anemia (DBA) is an inherited disorder characterized by defects in erythropoiesis, congenital abnormalities, and predisposition to cancer. Approximately 25% of DBA patients have a mutation in RPS19, which encodes a component of the 40S ribosomal subunit. Upregulation of p53 contributes to the pathogenesis of DBA, but the link between ribosomal protein mutations and erythropoietic defects is not well understood. We found that RPS19 deficiency in hematopoietic progenitor cells leads to decreased GATA1 expression in the erythroid progenitor population and p53-dependent upregulation of tumor necrosis factor-a (TNF-a) in nonerythroid cells. The decrease in GATA1 expression was mediated, at least in part, by activation of p38 MAPK in erythroid cells and rescued by inhibition of TNF-a or p53. The anemia phenotype in rps19-deficient zebrafish was reversed by treatment with the TNF-a inhibitor etanercept. Our data reveal that RPS19 deficiency leads to inflammation, p53-dependent increase in TNF-a, activation of p38 MAPK, and decreased GATA1 expression, suggesting a novel mechanism for the erythroid defects observed in DBA. (Blood. 2014;124(25):3791-3798)

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“…6 Diamond-Blackfan anemia (DBA) is characterized by severe hyporegenerative, macrocytic anemia with erythroblastopenia, 7 and variably associated congenital malformations, growth retardation, and elevations in erythrocyte adenosine deaminase and/or hemoglobin F levels. 8,9 In 50% to 60% of DBA patients, mutations in ribosomal protein (RP) genes or GATA1 are found, with a high frequency of sporadic cases because of de novo mutations. [10][11][12] The majority of patients respond to an initial course of corticosteroid (CS) therapy, and ;20% of all patients enter a steroid-and transfusion-free "remission" by adulthood.…”

Section: Introductionmentioning

confidence: 99%