Diamond-Blackfan anemia causes
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Overview
Diamond-Blackfan anemia is caused by heterozygous mutation in a gene encoding a small (RPS7, RPS10, RPS15A, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27, RPS28, RPS29) or large (RPL5, RPL11, RPL15, RPL17, RPL19, RPL26, RPL27, RPL31, RPL35A) ribosomal subunit-associated protein in 80%-85% of the affected cases of DBA. 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 and may account for the DBA phenotype.
Causes
Genetics
- In about 80-85% of cases Diamond-Blackfan anemia, a block in erythropoiesis occurs due to the ribosomal protein gene mutation. Ribosomal protein mutations are sprodaic(55%) or hereditary. Sporadic mutation occurs in genes encoding several different ribosomal proteins.
- About 25% of patients have mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2. RPS19 has an important role in 18S rRNA maturation in yeast and in human cells.
- Other mutated genes have 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 small or large ribosomal subunit synthesis deficiencies in human cells.
- Mutation of "Non-RP" genes such as TSR2 and GATA1, and EPO also were found.[1][2][3][4][5]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 of other erythroid genes. Approximately 40-45 % DBA cases are inherited with an autosomal dominant inheritance.[6][7][8][9] and they have a family history of the disease with varying phenotypes.[1], although some of cases (GATA1-related DBA and TSR2-related DBA) are inherited in an X-linked manner.[10].Also, autosomal recessive inheritance, with a lesser frequency has been reported.[11]Variable expressivity is seen in all RP gene mutations. Possible mechanisms underlying variable expressivity include an influence of modifier genes and environmental factors. [12]
- 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 and may account for the DBA phenotype. [1]
References
- ↑ 1.0 1.1 1.2 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.
- ↑ Sankaran VG, Ghazvinian R, Do R, Thiru P, Vergilio JA, Beggs AH, Sieff CA, Orkin SH, Nathan DG, Lander ES, Gazda HT (July 2012). "Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia". J. Clin. Invest. 122 (7): 2439–43. doi:10.1172/JCI63597. PMC 3386831. PMID 22706301.
- ↑ Klar J, Khalfallah A, Arzoo PS, Gazda HT, Dahl N (September 2014). "Recurrent GATA1 mutations in Diamond-Blackfan anaemia". Br. J. Haematol. 166 (6): 949–51. doi:10.1111/bjh.12919. PMID 24766296.
- ↑ Khajuria RK, Munschauer M, Ulirsch JC, Fiorini C, Ludwig LS, McFarland SK, Abdulhay NJ, Specht H, Keshishian H, Mani DR, Jovanovic M, Ellis SR, Fulco CP, Engreitz JM, Schütz S, Lian J, Gripp KW, Weinberg OK, Pinkus GS, Gehrke L, Regev A, Lander ES, Gazda HT, Lee WY, Panse VG, Carr SA, Sankaran VG (March 2018). "Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis". Cell. 173 (1): 90–103.e19. doi:10.1016/j.cell.2018.02.036. PMC 5866246. PMID 29551269.
- ↑ Kim AR, Ulirsch JC, Wilmes S, Unal E, Moraga I, Karakukcu M, Yuan D, Kazerounian S, Abdulhay NJ, King DS, Gupta N, Gabriel SB, Lander ES, Patiroglu T, Ozcan A, Ozdemir MA, Garcia KC, Piehler J, Gazda HT, Klein DE, Sankaran VG (March 2017). "Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation". Cell. 168 (6): 1053–1064.e15. doi:10.1016/j.cell.2017.02.026. PMC 5376096. PMID 28283061.
- ↑ Ulirsch JC, Verboon JM, Kazerounian S, Guo MH, Yuan D, Ludwig LS, Handsaker RE, Abdulhay NJ, Fiorini C, Genovese G, Lim ET, Cheng A, Cummings BB, Chao KR, Beggs AH, Genetti CA, Sieff CA, Newburger PE, Niewiadomska E, Matysiak M, Vlachos A, Lipton JM, Atsidaftos E, Glader B, Narla A, Gleizes PE, O'Donohue MF, Montel-Lehry N, Amor DJ, McCarroll SA, O'Donnell-Luria AH, Gupta N, Gabriel SB, MacArthur DG, Lander ES, Lek M, Da Costa L, Nathan DG, Korostelev AA, Do R, Sankaran VG, Gazda HT (December 2018). "The Genetic Landscape of Diamond-Blackfan Anemia". Am. J. Hum. Genet. 103 (6): 930–947. doi:10.1016/j.ajhg.2018.10.027. PMC 6288280. PMID 30503522.
- ↑ 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.
- ↑ 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.
- ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Clinton C, Gazda HT. PMID 20301769. Vancouver style error: initials (help); Missing or empty
|title=(help) - ↑ Engidaye G, Melku M, Enawgaw B (March 2019). "Diamond Blackfan Anemia: Genetics, Pathogenesis, Diagnosis and Treatment". EJIFCC. 30 (1): 67–81. PMC 6416817. PMID 30881276.
- ↑ 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.