The Genetic Landscape of Diamond-Blackfan Anemia

Ulirsch, Jacob C.; Verboon, Jeffrey M.; Kazerounian, Shiva; Guo, Michael H.; Yuan, Daniel; Ludwig, Leif S.; Handsaker, Robert E.; Abdulhay, Nour J.; Fiorini, Claudia; Genovese, Giulio; Lim, Elaine T.; Cheng, Aaron M.; Cummings, Beryl B.; Chao, Katherine R.; Beggs, Alan H.; Genetti, Casie A.; Sieff, Colin A.; Newburger, Peter E.; Niewiadomska, Edyta; Matysiak, Michał; Vlachos, Adrianna; Lipton, Jeffrey M.; Atsidaftos, Eva; Glader, Bertil; Narla, Anupama; Gleizes, Pierre‐Emmanuel; O’Donohue, Marie-Françoise; Montel-Lehry, Nathalie; Amor, David J.; McCarroll, Steven A.; O’Donnell-Luria, Anne H.; Gupta, Namrata; Gabriel, Stacey; MacArthur, Daniel G.; Lander, Eric S.; Lek, Monkol; Costa, Lydie Da; Nathan, David G.; Коростелев, А.A.; Do, Ron; Sankaran, Vijay G.; Gazda, Hanna T.

doi:10.1016/j.ajhg.2018.12.011

Cited by 42 publications

(63 citation statements)

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“…This is an inherited bone marrow failure syndrome characterized by anemia, macrocytosis, reticulopenia, and selective reduction or absence of erythroid precursors (BFU‐Es) in an otherwise normocellular bone marrow . More than 200 heterozygous mutations in 19 ribosomal protein (RP) genes have been recorded to‐date, accounting for most (approximately 70%), but not all, of the DBA cases . Sankaran and colleagues were the first to identify through exome sequencing a GATA1 mutation associated with DBA .…”

Section: Downregulation Of Gata1 Protein Levels and Ineffective Erythmentioning

confidence: 99%

Regulation of GATA1 levels in erythropoiesis

et al. 2019

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GATA1 is considered as the "master" transcription factor in erythropoiesis. It regulates at the transcriptional level all aspects of erythroid maturation and function, as revealed by gene knockout studies in mice and by genome-wide occupancies in erythroid cells. The GATA1 protein contains two zinc finger domains and an N-terminal transactivation domain. GATA1 translation results in the production of the full-length protein and of a shorter variant (GATA1s) lacking the N-terminal transactivation domain, which is functionally deficient in supporting erythropoiesis. GATA1 protein abundance is highly regulated in erythroid cells at different levels, including transcription, mRNA translation, posttranslational modifications, and protein degradation, in a differentiationstage-specific manner. Maintaining high GATA1 protein levels is essential in the early stages of erythroid maturation, whereas downregulating GATA1 protein levels is a necessary step in terminal erythroid differentiation. The importance of maintaining proper GATA1 protein homeostasis in erythropoiesis is demonstrated by the fact that both GATA1 loss and its overexpression result in lethal anemia. Importantly, alterations in any of those GATA1 regulatory checkpoints have been recognized as an important cause of hematological disorders such as dyserythropoiesis (with or without thrombocytopenia), β-thalassemia, Diamond-Blackfan anemia, myelodysplasia, or leukemia. In this review, we provide an overview of the multilevel regulation of GATA1 protein homeostasis in erythropoiesis and of its deregulation in hematological disease. K E Y W O R D S

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Section: Downregulation Of Gata1 Protein Levels and Ineffective Erythmentioning

confidence: 99%

Regulation of GATA1 levels in erythropoiesis

et al. 2019

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“…While many of the examples discussed above emerged through traditional family‐based linkage or sequencing analyses, as larger cohorts of rare disease patients are being assembled, broader assessments through RVAS and gene burden analyses are occurring. Such approaches have been valuable in the context of DBA (Ulirsch et al , ), as well as for studies of patients with rare congenital forms of thrombocytopenia and immunodeficiencies (preprint: Downes et al , , preprint: Thaventhiran et al , ). There is no doubt that as larger collaborative efforts are established for rare disease patients, including those with genetic blood disorders, there will be more opportunities to identify additional causal and modifier genes.…”

Section: Introductionmentioning

confidence: 99%

“…There is no doubt that as larger collaborative efforts are established for rare disease patients, including those with genetic blood disorders, there will be more opportunities to identify additional causal and modifier genes. Moreover, these studies highlight the incomplete penetrance or variable expressivity of many alleles when examined in large cohorts of patients compared with healthy population controls (Ulirsch et al , ). Such discoveries will pave the way for further insights into human hematopoiesis.…”

Section: Introductionmentioning

confidence: 99%

The genetics of human hematopoiesis and its disruption in disease

2019

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Hematopoiesis, or the process of blood cell production, is a paradigm of multi‐lineage cellular differentiation that has been extensively studied, yet in many aspects remains incompletely understood. Nearly all clinically measured hematopoietic traits exhibit extensive variation and are highly heritable, underscoring the importance of genetic variation in these processes. This review explores how human genetics have illuminated our understanding of hematopoiesis in health and disease. The study of rare mutations in blood and immune disorders has elucidated novel roles for regulators of hematopoiesis and uncovered numerous important molecular pathways, as seen through examples such as Diamond‐Blackfan anemia and the GATA2 deficiency syndromes. Additionally, population studies of common genetic variation have revealed mechanisms by which human hematopoiesis can be modulated. We discuss advances in functionally characterizing common variants associated with blood cell traits and discuss therapeutic insights, such as the discovery of BCL11A as a modulator of fetal hemoglobin expression. Finally, as genetic techniques continue to evolve, we discuss the prospects, challenges, and unanswered questions that lie ahead in this burgeoning field.

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“…Beckmann, N. Katsanis, C.V. Nicchitta, F. Fellman, unpublished data), and genes identified within genetic deletions (e.g. RPS8 , RPS14 ) (Gazda et al , ; Ulirsch et al , ). Herein, 55% are sporadic ( de novo ) mutations and 45% comprise familial mutations, concerning both affected family members as well as asymptomatic (“silent”) carriers, reflecting the variable penetration of RP gene mutations.…”

Section: Diagnosismentioning

confidence: 99%

“…Given that RPS19 is the most frequently mutated gene (25% of cases), genetic screening often begins with targeted Sanger sequencing of RPS19 . However, as a consequence of improved accessibility to newly developed genetic methods, many laboratories nowadays use next generation sequencing (NGS, targeted or whole exome) to analyse gene panels of commonly mutated genes in DBA, or all genes that have been linked to DBA (Da Costa et al , ), including mutations in non‐ribosomal genes, such as GATA1 , TSR2, ADA2 , and the recently described biallelic mutations in erythropoietin (EPO) (Sankaran et al , ; Parrella et al , ; Ulirsch et al , ). However, whereas mutations in GATA1 and TSR2 have been directly linked to ribosome biogenesis or function, and are therefore generally considered DBA‐specific, it makes sense to classify mutations in other non‐RP genes separately (Ludwig et al , ; Van Montfrans et al , ; Khajuria et al , ; Schutz et al , ).…”

Section: Diagnosismentioning

confidence: 99%

How I manage children with Diamond‐Blackfan anaemia

Bartels

Bierings

2018

Br J Haematol

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Summary Diamond‐Blackfan anaemia ( DBA ) is a rare inherited marrow failure disorder, characterized by hypoplastic anaemia, congenital anomalies and a predisposition to cancer as a result of ribosomal dysfunction. Historically, treatment is based on glucocorticoids and/or blood transfusions, which is accompanied by significant toxicity and long‐term sequelae. Currently, stem cell transplantation is the only curative option for the haematological DBA phenotype. Whereas this procedure has been quite successful in the last decade in selected patients, novel therapies and biological insights are still warranted to improve clinical care for all DBA patients. In addition to paediatric haematologists, other physicians (e.g. endocrinologist, gynaecologist) should ideally be involved in the care of this chronic condition from an early age, to improve lifelong management of haematological and non‐haematological symptoms, and screen for DBA ‐associated malignancies. Here we provide an overview of current knowledge and recommendations for the day‐to‐day care of DBA patients.

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The Genetic Landscape of Diamond-Blackfan Anemia

Abstract: Pearson marrow pancreas syndrome in patients suspected to have Diamond-Blackfan anemia. Blood 17, 437-440. The authors apologize for this error.

Cited by 42 publications

References 0 publications

Regulation of GATA1 levels in erythropoiesis

Regulation of GATA1 levels in erythropoiesis

The genetics of human hematopoiesis and its disruption in disease

How I manage children with Diamond‐Blackfan anaemia

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