Journal of Interdisciplinary Genomics

Interdisciplinary Society of Genetic & Genomic Medicine (유전의학융합회)
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Exploring the Genetic Mechanisms Underlying Diamond-Blackfan Anemia

  • Ye Jee Shim (Department of Pediatrics, Keimyung University School of Medicine, Keimyung University Dongsan Hospital)
  • Received : 2024.09.12
  • Accepted : 2024.10.21
  • Published : 2024.10.31
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Abstract

Diamond-Blackfan Anemia (DBA) is a rare congenital bone marrow failure syndrome primarily characterized by erythroblastopenia and macrocytic anemia. This disorder results from mutations in ribosomal protein (RP) genes, which lead to defective ribosomal RNA maturation, nucleolar stress, and impaired erythropoiesis. Mutations in RP genes have been identified, with RPS19 being the most commonly affected gene, accounting for approximately 25% of all cases. Other frequently mutated genes include RPL5, RPL11, and RPS26. These mutations are mostly heterozygous and cause defective ribosome assembly and biogenesis, which activates the p53 pathway, resulting in cell cycle arrest and apoptosis. In addition, non-RP gene mutations, such as those in GATA1, TSR2, or HEATR3, have been linked to DBA-like phenotypes, further complicating the genetic landscape. Congenital malformations, particularly craniofacial anomalies, thumb abnormalities, and cardiac defects, are common in patients with specific RP gene mutations, such as RPL5 and RPL11. Advances in next-generation sequencing have improved the identification of novel mutations; however, approximately 20-25% of DBA cases remain genetically unexplained. In this review, we explore the genetic landscape of DBA and provide insights into the underlying mutations and their contributions to disease pathophysiology.

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References

  1. Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, et al. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol 2008;142(6):859-76. doi: 10.1111/j.1365-2141.2008.07269.x. 
  2. Vlachos A, Muir E. How I treat Diamond-Blackfan anemia. Blood 2010;116(19):3715-23. doi: 10.1182/blood-2010-02-251090. 
  3. Ulirsch JC, Verboon JM, Kazerounian S, Guo MH, Yuan D, Ludwig LS, et al. The genetic landscape of Diamond-Blackfan Anemia. Am J Hum Genet 2018;103(6):930-47. doi: 10.1016/j.ajhg.2018.10.027. 
  4. Sankaran VG, Ghazvinian R, Do R, Thiru P, Vergilio JA, Beggs AH, et al. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest 2012;122(7):2439-43. doi: 10.1172/jci63597. 
  5. Gripp KW, Curry C, Olney AH, Sandoval C, Fisher J, Chong JX, et al. Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28. Am J Med Genet A 2014;164a(9):2240-9. doi: 10.1002/ajmg.a.36633. 
  6. O'Donohue MF, Da Costa L, Lezzerini M, Unal S, Joret C, Bartels M, et al. HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia. Blood 2022;139(21):3111-26. doi: 10.1182/blood.2021011846. 
  7. Martinez Barrio A, Eriksson O, Badhai J, Frojmark AS, BongcamRudloff E, Dahl N, et al. Targeted resequencing and analysis of the Diamond-Blackfan anemia disease locus RPS19. PLoS One 2009;4(7):e6172. doi: 10.1371/journal.pone.0006172. 
  8. Fox JM, Rashford RL, Lindahl L. Co-assembly of 40S and 60S ribosomal proteins in early steps of eukaryotic ribosome assembly. Int J Mol Sci 2019;20(11). doi: 10.3390/ijms20112806. 
  9. Dorner K, Badertscher L, Horvath B, Hollandi R, Molnar C, Fuhrer T, et al. Genome-wide RNAi screen identifies novel players in human 60S subunit biogenesis including key enzymes of polyamine metabolism. Nucleic Acids Res 2022;50(5):2872-88. doi: 10.1093/nar/gkac072. 
  10. Flygare J, Aspesi A, Bailey JC, Miyake K, Caffrey JM, Karlsson S, et al. Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Blood 2007;109(3):980-6. doi: 10.1182/blood-2006-07-038232. 
  11. Le Goff S, Boussaid I, Floquet C, Raimbault A, Hatin I, AndrieuSoler C, et al. p53 activation during ribosome biogenesis regulates normal erythroid differentiation. Blood 2021;137(1):89-102. doi: 10.1182/blood.2019003439. 
  12. Boria I, Garelli E, Gazda HT, Aspesi A, Quarello P, Pavesi E, et al. The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update. Hum Mutat 2010;31(12):1269-79. doi: 10.1002/humu.21383. 
  13. Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I, et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet 1999;21(2):169-75. doi: 10.1038/5951. 
  14. Willig TN, Draptchinskaia N, Dianzani I, Ball S, Niemeyer C, Ramenghi U, et al. Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression. Blood 1999;94(12):4294-306. 
  15. Campagnoli MF, Ramenghi U, Armiraglio M, Quarello P, Garelli E, Carando A, et al. RPS19 mutations in patients with Diamond-Blackfan anemia. Hum Mutat 2008;29(7):911-20. doi: 10.1002/humu.20752. 
  16. Gazda HT, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton JM, et al. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet 2006;79(6):1110-8. doi: 10.1086/510020. 
  17. Choesmel V, Fribourg S, Aguissa-Toure AH, Pinaud N, Legrand P, Gazda HT, et al. Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder. Hum Mol Genet 2008;17(9):1253-63. doi: 10.1093/hmg/ddn015. 
  18. Cmejla R, Cmejlova J, Handrkova H, Petrak J, Pospisilova D. Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia. Hum Mutat 2007;28(12):1178-82. doi: 10.1002/humu.20608. 
  19. Watkins-Chow DE, Cooke J, Pidsley R, Edwards A, Slotkin R, Leeds KE, et al. Mutation of the diamond-blackfan anemia gene Rps7 in mouse results in morphological and neuroanatomical phenotypes. PLoS Genet 2013;9(1):e1003094. doi: 10.1371/journal.pgen.1003094. 
  20. Akram T, Fatima A, Klar J, Hoeber J, Zakaria M, Tariq M, et al. Aberrant splicing due to a novel RPS7 variant causes DiamondBlackfan Anemia associated with spontaneous remission and meningocele. Int J Hematol 2020;112(6):894-9. doi: 10.1007/s12185-020-02950-6. 
  21. Doherty L, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Clinton C, et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet 2010;86(2):222-8. doi: 10.1016/j.ajhg.2009.12.015. 
  22. Gerrard G, Valganon M, Foong HE, Kasperaviciute D, Iskander D, Game L, et al. Target enrichment and high-throughput sequencing of 80 ribosomal protein genes to identify mutations associated with Diamond-Blackfan anaemia. Br J Haematol 2013;162(4):530-6. doi: 10.1111/bjh.12397. 
  23. Mirabello L, Macari ER, Jessop L, Ellis SR, Myers T, Giri N, et al. Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families. Blood 2014;124(1):24-32. doi: 10.1182/blood-2013-11-540278. 
  24. Ikeda F, Yoshida K, Toki T, Uechi T, Ishida S, Nakajima Y, et al. Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia. Haematologica 2017;102(3):e93-e6. doi: 10.3324/haematol.2016.153932. 
  25. Wang R, Yoshida K, Toki T, Sawada T, Uechi T, Okuno Y, et al. Loss of function mutations in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan anaemia. Br J Haematol 2015;168(6):854-64. doi: 10.1111/bjh.13229. 
  26. Gazda HT, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Schneider H, et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in DiamondBlackfan anemia patients. Am J Hum Genet 2008;83(6):769-80. doi: 10.1016/j.ajhg.2008.11.004. 
  27. Farrar JE, Nater M, Caywood E, McDevitt MA, Kowalski J, Takemoto CM, et al. Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia. Blood 2008;112(5):1582-92. doi: 10.1182/blood-2008-02-140012. 
  28. Gazda HT, Preti M, Sheen MR, O'Donohue MF, Vlachos A, Davies SM, et al. Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific preribosomal RNA processing defect in diamond-blackfan anemia. Hum Mutat 2012;33(7):1037-44. doi: 10.1002/humu.22081. 
  29. Landowski M, O'Donohue MF, Buros C, Ghazvinian R, MontelLehry N, Vlachos A, et al. Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum Genet 2013;132(11):1265-74. doi: 10.1007/s00439-013-1326-z. 
  30. Wlodarski MW, Da Costa L, O'Donohue MF, Gastou M, Karboul N, Montel-Lehry N, et al. Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia. Haematologica 2018;103(6):949-58. doi: 10.3324/haematol.2017.177980. 
  31. Mirabello L, Khincha PP, Ellis SR, Giri N, Brodie S, Chandrasekharappa SC, et al. Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation. J Med Genet 2017;54(6):417-25. doi: 10.1136/jmedgenet-2016-104346. 
  32. Ling T, Crispino JD. GATA1 mutations in red cell disorders. IUBMB Life 2020;72(1):106-18. doi: 10.1002/iub.2177. 
  33. Boultwood J, Pellagatti A. Reduced translation of GATA1 in Diamond-Blackfan anemia. Nat Med 2014;20(7):703-4. doi: 10.1038/nm.3630. 
  34. Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, et al. Altered translation of GATA1 in Diamond-Blackfan anemia. Nat Med 2014;20(7):748-53. doi: 10.1038/nm.3557. 
  35. Rio S, Gastou M, Karboul N, Derman R, Suriyun T, Manceau H, et al. Regulation of globin-heme balance in Diamond-Blackfan anemia by HSP70/GATA1. Blood 2019;133(12):1358-70. doi: 10.1182/blood-2018-09-875674. 
  36. Yang YM, Karbstein K. The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress. Sci Adv 2022;8(8):eabl4386. doi: 10.1126/sciadv.abl4386. 
  37. Iskander D, Warren AJ. Turning up the HEAT(R3) in DiamondBlackfan anemia. Blood 2022;139(21):3101-2. doi: 10.1182/blood.2022015881.