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 in about 80-85% of those affected. Sporadic mutation(55%) occurs in genes encoding several different ribosomal proteins, although based on the latest studies, approximately 40 – 45% of DBA cases are hereditary which are inherited with an autosomal dominant inheritance, means that a single copy of an altered gene in each cell is adequate to cause the disorder and is inherited from one affected parent.[1][2] and they have a family history of the disease with varying phenotypes.[3] about 25% of patients have mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2. RPS19 protein has been demonstrated to play an important role in 18S rRNA maturation in yeast and in human cells. 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, that result in alterations of pre-RNA processing and small or large ribosomal subunit synthesis which were demonstrated in human cells with RPL11, RPL35A, RPS24, and RPL26, RPS7 deficiency[4] , also "non-RP" genes such as TSR2 and GATA1. TSR2 plays a role in ribosome biogenesis since it is involved in the pre-rRNA processing and binds to RPS26.GATA1 which is the major erythroid transcription factor as being essential for precursor cells to differentiate into red blood cells and plays a critical role in regulating normal erythroid differentiation by activating an array of erythroid genes. Researchers found DBA mutations reduce the actual numbers of ribosomes in blood precursor cells. Without enough ribosomes, the precursors can’t produce enough GATA1, so mature red cells never form. Other blood cells — like platelets, T cells, and B cells — can still develop since they’re not dependent on GATA1.[5] In the remaining 10-15% of DBA cases, no abnormal genes have yet been identified. It is likely that mutations are in a regulatory region including intronic regions and promoters in one of the known RP genes may account for the DBA phenotype. [3]
- Mutations in RP genes have been confirmed to be the direct cause of faulty erythropoiesis and anemia.[6].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 . in ‘‘ribosomal stress, 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. Mutated RP genes 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.[7]
References
- ↑ Ball S (2011). "Diamond Blackfan anemia". Hematology Am Soc Hematol Educ Program. 2011: 487–91. doi:10.1182/asheducation-2011.1.487. PMID 22160079.
- ↑ 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.
- ↑ 3.0 3.1 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.
- ↑ Choesmel V, Fribourg S, Aguissa-Touré AH, Pinaud N, Legrand P, Gazda HT, Gleizes PE (May 2008). "Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder". Hum. Mol. Genet. 17 (9): 1253–63. doi:10.1093/hmg/ddn015. PMID 18230666.
- ↑ Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, George TI, Gotlib JR, Beggs AH, Sieff CA, Lodish HF, Lander ES, Sankaran VG (July 2014). "Altered translation of GATA1 in Diamond-Blackfan anemia". Nat. Med. 20 (7): 748–53. doi:10.1038/nm.3557. PMC 4087046. PMID 24952648.
- ↑ 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.
- ↑ 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.