Diamond-Blackfan anemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
- Diamond Blackfan anemia is characterized by a block in erythropoiesis which is due to the ribosomal protein gene mutation.DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes.[1] about 25% of patients have mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2 which is responsible for a defect in rRNA maturation. However, the disease characterized by genetic heterogeneity and other mutated genes also been found in RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS24, and RPS26, and rarely in RPL15, RPL17, RPL19, RPL26, RPL27, RPL31, RPS15A, RPS20, RPS27, RPS28, RPS29, and TSR2. In a few patients, the disease is caused by a mutation in the GATA1 gene. In the remaining 10-15% of patients, no abnormal genes have yet been identified.
A generally documented pathogenetic hypothesis implies that a defective ribosome biosynthesis leads to apoptosis in erythroid progenitors which in turn is leading to erythroid failure. This mechanism has been named ‘‘ribosomal stress’’, and there are indications that it may be signaled through p53.DBA have led to the formulation of “ribosomal stress” hypothesis in which reduced RP synthesis activates p53 that induces the downstream events and leads to cell cycle termination or apoptosis. Finally, this phenomenon results in the DBA phenotype of anemia, deprived growth and results in congenital abnormalities All genes identified to be mutated in DBA encode ribosomal proteins which are involved in either the small (RPS) or large (RPL) subunits of these proteins and the scarcity of these proteins can cause the development of the disease.[2] [2]
Based on the latest studies, approximately 40 – 45% of DBA cases are hereditary which are inherited with autosomal dominant inheritance which means that a single copy of an altered gene in each cell is adequate to cause the disorder.[3], whereas the remaining 55 – 60% of the affected patients are sporadic, i.e., resulted from new aberrations in the gene which occur in people who have no history of this disorder in their family [4]
Mutations in RP genes have been confirmed to be the direct cause of faulty erythropoiesis and consequently anemia, and are found in more than half of DBA cases. [5]
Genetics
Approximately 10-25% of DBA cases have a family history of disease, and most pedigrees suggest an autosomal dominant mode of inheritance. The disease is characterized by genetic heterogeneity, with current evidence supporting the existence of at least three genes mutated in DBA. In 1997, a patient was identified who carried a rare balanced chromosomal translocation involving chromosome 19 and the X chromosome. This suggested that the affected gene might lie in one of the two regions that were disrupted by this cytogenetic anomaly. Linkage analysis in affected families also implicated this region in disease, and led to the cloning of the first DBA gene. About 20-25% of DBA cases are caused by mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2. Interestingly, some previously undiagnosed relatives of DBA patients were found to carry mutations. These patients also had increased adenosine deaminase levels in their red blood cells but no other overt signs of disease. A subsequent study of families with no evidence of RPS19 mutations determined that 18 of 38 families showed evidence for involvement of an unknown gene on chromosome 8 at 8p23.3-8p22. The precise genetic defect in these families has not yet been delineated. In a further 7 families, both the chromosome 19 and chromosome 8 loci could be excluded for involvement, suggesting the existence of at least one other DBA locus in the human genome.
Molecular Basis
The phenotype of DBA patients suggests a hematological stem cell defect specifically affecting the erythroid progenitor population. This is difficult to reconcile with the known function of the single known DBA gene. The RPS19 protein is involved in the production of ribosomes. As such, loss of RPS19 function would be predicted to affect translation and protein biosynthesis and have a much broader impact. Disease features may be related to the nature of RPS19 mutations. The disease is characterized by dominant inheritance, and therefore arises due to a partial loss of RPS19 protein function. It is possible that erythroid progenitors are acutely sensitized to this decreased function, while most other tissues are unaffected.
References
- ↑ Da Costa L, Narla A, Mohandas N (2018). "An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia". F1000Res. 7. doi:10.12688/f1000research.15542.1. PMC 6117846. PMID 30228860.
- ↑ 2.0 2.1 Lipton JM, Ellis SR (April 2009). "Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis". Hematol. Oncol. Clin. North Am. 23 (2): 261–82. doi:10.1016/j.hoc.2009.01.004. PMC 2886591. PMID 19327583.
- ↑ Garçon L, Ge J, Manjunath SH, Mills JA, Apicella M, Parikh S, Sullivan LM, Podsakoff GM, Gadue P, French DL, Mason PJ, Bessler M, Weiss MJ (August 2013). "Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients". Blood. 122 (6): 912–21. doi:10.1182/blood-2013-01-478321. PMC 3739037. PMID 23744582.
- ↑ Ball S (2011). "Diamond Blackfan anemia". Hematology Am Soc Hematol Educ Program. 2011: 487–91. doi:10.1182/asheducation-2011.1.487. PMID 22160079.
- ↑ Vlachos A, Dahl N, Dianzani I, Lipton JM (October 2013). "Clinical utility gene card for: Diamond-Blackfan anemia--update 2013". Eur. J. Hum. Genet. 21 (10). doi:10.1038/ejhg.2013.34. PMC 3778360. PMID 23463023.