Diamond–Blackfan Anaemia: From Genotype to Phenotype

Abstract

Diamond–Blackfan anaemia (DBA) is a congenital disorder that presents in the first year of life as severe anaemia, and in several patients is coupled with developmental defects. DBA is a ribosomopathy because almost all known mutations or deletions occur in genes encoding ribosomal proteins (RPs) that impair ribosome biogenesis. However, atypical examples of patients carry mutations in the erythroid specific transcription factor GATA1. DBA is a rare disease that displays a high level of heterogeneity with respect to the affected RP and disease penetrance. The reduced availability of ribosomes affects several cellular processes, including stabilisation of the p53 tumour suppressor, and impaired messenger ribonucleic acid (mRNA) translation. Registration of the genetic and phenotypic characteristics of DBA patients worldwide is needed to understand the relation between mutations, patient symptoms and cellular processes that underlie this pathophysiology.

Key Concepts

  • Diamond–Blackfan anaemia (DBA) is caused by haploinsufficiency of one of several ribosomal proteins in at least two‐thirds of all patients; the disease causing mutation is unknown in approximately 30% of patients.
  • The mechanisms underlying the ribosomopathy DBA are multiple, and are incompletely understood.
  • Particularly, the roles of transcript specific translation and iron homeostasis are underestimated.
  • Defective mRNA translation in ribosomopathies such as DBA should be investigated in cells that are affected in the disease, because an mRNA translation defect depends on the cell's specific transcriptome.
  • DBA type I and DBA type II should be used to distinguish between patients carrying RP mutations versus those carrying mutations in genes that specifically affect erythropoiesis including GATA1.
  • The ribosomopathy Diamond–Blackfan anaemia should be renamed to Diamond–Blackfan syndrome to emphasise that it is a systemic disease of which severe anaemia at young age is the most common, but not the exclusive symptom.
  • The heterogeneity with which DBA presents, even when family members carry the same mutation, needs to be investigated to find a proper treatment for severe DBA.

Keywords: ribosomopathy; ribosome biogenesis; ribosomal proteins; TP53; mRNA translation; Gata1

Figure 1. Ribosome biogenesis. Duplicated rRNA genes are transcribed by RNA polymerase‐I (Pol‐I) in the nucleoli to produce the 47S pre‐rRNA. Pol‐III transcribes 5S rRNA in the nucleus and Pol‐II is required to transcribe RP genes. RP mRNA is translated in the cytoplasm and subsequently transported to the nucleolus where ribosomes are synthesised. RPs (blue and red), the pre‐RNA and accessory proteins (green) first form the 90S pre‐ribosome. Part of the RPs cooperates with enzymes and small nucleolar RNAs (snoRNA) in the processing of the pre‐rRNA. Cleavage of the 47S pre‐rRNA into a 21S and a 32S pre‐rRNA generates the pre‐40S and pre‐60S ribosomal subunits. Inclusion of 5S rRNA into the large ribosomal subunit is mediated by RPL5 and RPL11. In several steps, the pre‐rRNAs are trimmed to produce the 18S rRNA of the small (40S) ribosomal subunit and the 5.8S plus 28S rRNA of the large (60S) ribosomal subunit. Immature ribosomes in the nucleolus associate with specific export complexes (including eIF6 for the 60S subunit) that translocate the subunits through the nucleus where they undergo further modifications and finally are exported to the cytoplasm where the final maturation steps take place (double line represents nuclear membrane). Liberated from the export complexes, the ribosomal subunits can join into a 80S ribosome during mRNA translation (for review, see Kressler et al., ).
Figure 2. Ribosomopathies. Several congenital diseases are associated with defects in ribosome biosynthesis. Treacher Collins (TC) is associated with reduced transcription of rRNA genes, whereas DBA is associated with loss of RPs that are required for rRNA processing. Both DBA and TC reduce ribosome biogenesis, resulting in an excess of RPs that sequester HDM2‐Mdm2 such that p53 is no longer ubiquitinated. Stabilisation increases p53 expression. Dyskeratosis congenita (DC) is characterised by impaired rRNA uridinylation and Shwachman–Diamond syndrome (SDS) is characterised by reduced release of the eIF6‐containing protein complex that exports the 60S ribosomal subunit to the cytoplasm. The distinct diseases impair the availability and/or function of ribosomes, which impacts differently on the transcriptome. Cell‐specific effects may be caused by selective sensitivity of a cell's transcriptome to the specific translation defect.
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References

Amanatiadou EP, Papadopoulos GL, Strouboulis J, et al. (2015) GATA1 and PU.1 bind to ribosomal protein genes in erythroid cells: implications for ribosomopathies. PLoS One 10 (10): e0140077.

Amsterdam A, Sadler KC, Lai K, et al. (2004) Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biology 2 (5): E139.

Antunes AT, Goos YJ, Pereboom TC, et al. (2015) Ribosomal protein mutations result in constitutive p53 protein degradation through impairment of the AKT pathway. PLoS Genetics 11 (7): e1005326.

Aspesi A, Pavesi E, Robotti E, et al. (2014) Dissecting the transcriptional phenotype of ribosomal protein deficiency: implications for Diamond‐Blackfan Anemia. Gene 545 (2): 282–289.

Badhai J, Frojmark AS, J Davey E, et al. (2009) Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond‐Blackfan anemia. Biochimica et Biophysica Acta 1792 (10): 1036–1042.

Betin VM, Singleton BK, Parsons SF, et al. (2013) Autophagy facilitates organelle clearance during differentiation of human erythroblasts: evidence for a role for ATG4 paralogs during autophagosome maturation. Autophagy 9 (6): 881–893.

Bolze A, Mahlaoui N, Byun M, et al. (2013) Ribosomal protein SA haploinsufficiency in humans with isolated congenital asplenia. Science 340 (6135): 976–978.

Brooks SS, Wall AL, Golzio C, et al. (2014) A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X‐linked microcephaly in humans. Genetics 198 (2): 723–733.

Chlon TM, McNulty M, Goldenson B, et al. (2015) Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression. Haematologica 100 (5): 575–584.

Cmejlova J, Dolezalova L, Pospisilova D, et al. (2006) Translational efficiency in patients with Diamond‐Blackfan anemia. Haematologica 91 (11): 1456–1464.

Danilova N, Sakamoto KM and Lin S (2011) Ribosomal protein L11 mutation in zebrafish leads to haematopoietic and metabolic defects. British Journal of Haematology 152 (2): 217–228.

Danilova N and Gazda HT (2015) Ribosomopathies: how a common root can cause a tree of pathologies. Disease Models & Mechanisms 8 (9): 1013–1026.

De Keersmaecker K, Atak ZK, Li N, et al. (2013) Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T‐cell acute lymphoblastic leukemia. Nature Genetics 45 (2): 186–190.

Donati G, Peddigari S, Mercer CA, et al. (2013) 5S ribosomal RNA is an essential component of a nascent ribosomal precursor complex that regulates the Hdm2‐p53 checkpoint. Cell Reports 4 (1): 87–98.

Draptchinskaia N, Gustavsson P, Andersson B, et al. (1999) The gene encoding ribosomal protein S19 is mutated in Diamond‐Blackfan anaemia. Nature Genetics 21 (2): 169–175.

Dutt S, Narla A, Lin K, et al. (2011) Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood 117 (9): 2567–2576.

Ebert BL, Lee MM, Pretz JL, et al. (2005) An RNA interference model of RPS19 deficiency in Diamond‐Blackfan anemia recapitulates defective hematopoiesis and rescue by dexamethasone: identification of dexamethasone‐responsive genes by microarray. Blood 105 (12): 4620–4626.

Ebert BL, Pretz J, Bosco J, et al. (2008) Identification of RPS14 as a 5q‐ syndrome gene by RNA interference screen. Nature 451 (7176): 335–339.

Fahl SP, Harris B, Coffey F, et al. (2015) Rpl22 loss impairs the development of B lymphocytes by activating a p53‐dependent checkpoint. Journal of Immunology 194 (1): 200–209.

Farrar JE and Dahl N (2011) Untangling the phenotypic heterogeneity of Diamond Blackfan anemia. Seminars in Hematology 48 (2): 124–135.

Farrar JE, Vlachos A, Atsidaftos E, et al. (2011) Ribosomal protein gene deletions in Diamond‐Blackfan anemia. Blood 118 (26): 6943–6951.

Finch AJ, Hilcenko C, Basse N, et al. (2011) Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman‐Diamond syndrome. Genes and Development 25 (9): 917–929.

Fumagalli S and Thomas G (2011) The role of p53 in ribosomopathies. Seminars in Hematology 48 (2): 97–105.

Gagne KE, Ghazvinian R, Yuan D, et al. (2014) Pearson marrow pancreas syndrome in patients suspected to have Diamond‐Blackfan anemia. Blood 124 (3): 437–440.

Garcon L, Ge J, Manjunath SH, et al. (2013) Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients. Blood 122 (6): 912–921.

Gazda HT, Sheen MR, Vlachos A, et al. (2008) Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond‐Blackfan anemia patients. American Journal of Human Genetics 83 (6): 769–780.

Gotz R, Wiese S, Takayama S, et al. (2005) Bag1 is essential for differentiation and survival of hematopoietic and neuronal cells. Nature Neuroscience 8 (9): 1169–1178.

Gripp KW, Curry C, Olney AH, et al. (2014) Diamond‐Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28. American Journal of Medical Genetics Part A 164A (9): 2240–2249.

Heijnen HF, van Wijk R, Pereboom TC, et al. (2014) Ribosomal protein mutations induce autophagy through S6 kinase inhibition of the insulin pathway. PLoS Genetics 10 (5): e1004371.

Horos R, Ijspeert H, Pospisilova D, et al. (2012) Ribosomal deficiencies in Diamond‐Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts. Blood 119 (1): 262–272.

Iolascon A, Heimpel H, Wahlin A, et al. (2013) Congenital dyserythropoietic anemias: molecular insights and diagnostic approach. Blood 122 (13): 2162–2166.

Jaako P, Flygare J, Olsson K, et al. (2011) Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond‐Blackfan anemia. Blood 118 (23): 6087–6096.

Jaako P, Debnath S, Olsson K, et al. (2012) Dietary L‐leucine improves the anemia in a mouse model for Diamond‐Blackfan anemia. Blood 120 (11): 2225–2228.

Jaako P, Debnath S, Olsson K, et al. (2015) Disruption of the 5S RNP‐Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond‐Blackfan anemia. Leukemia 29 (11): 2221–2229.

Jones NC, Lynn ML, Gaudenz K, et al. (2008) Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nature Medicine 14 (2): 125–133.

Keel SB, Doty RT, Yang Z, et al. (2008) A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 319 (5864): 825–828.

Klauck SM, Felder B, Kolb‐Kokocinski A, et al. (2006) Mutations in the ribosomal protein gene RPL10 suggest a novel modulating disease mechanism for autism. Molecular Psychiatry 11 (12): 1073–1084.

Kondrashov N, Pusic A, Stumpf CR, et al. (2011) Ribosome‐mediated specificity in Hox mRNA translation and vertebrate tissue patterning. Cell 145 (3): 383–397.

Kressler D, Hurt E and Bassler J (2010) Driving ribosome assembly. Biochimica et Biophysica Acta 1803 (6): 673–683.

Kumar MS, Narla A, Nonami A, et al. (2011) Coordinate loss of a microRNA and protein‐coding gene cooperate in the pathogenesis of 5q‐ syndrome. Blood 118 (17): 4666–4673.

Lai K, Amsterdam A, Farrington S, et al. (2009) Many ribosomal protein mutations are associated with growth impairment and tumor predisposition in zebrafish. Developmental Dynamics 238 (1): 76–85.

von Lindern M, Deiner EM, Dolznig H, et al. (2001) Leukemic transformation of normal murine erythroid progenitors: v‐ and c‐ErbB act through signaling pathways activated by the EpoR and c‐Kit in stress erythropoiesis. Oncogene 20 (28): 3651–3664.

Ludwig LS, Gazda HT, Eng JC, et al. (2014) Altered translation of GATA1 in Diamond‐Blackfan anemia. Nature Medicine 20 (7): 748–753.

MacInnes AW, Amsterdam A, Whittaker CA, et al. (2008) Loss of p53 synthesis in zebrafish tumors with ribosomal protein gene mutations. Proceedings of the National Academy of Sciences of the United States of America 105 (30): 10408–10413.

Matsson H, Davey EJ, Frojmark AS, et al. (2006) Erythropoiesis in the Rps19 disrupted mouse: analysis of erythropoietin response and biochemical markers for Diamond‐Blackfan anemia. Blood Cells, Molecules & Diseases 36 (2): 259–264.

Mercurio S, Aspesi A, Silengo L, et al. (2016) Alteration of heme metaboism in a cellular model of Diamond‐Blackfan anemia. European Journal of Haematology 96 (4): 367–374, doi: 10.1111/ejh.12599.

Mihailovich M, Militti C, Gabaldon T, et al. (2010) Eukaryotic cold shock domain proteins: highly versatile regulators of gene expression. Bioessays 32 (2): 109–118.

Miyake K, Utsugisawa T, Flygare J, et al. (2008) Ribosomal protein S19 deficiency leads to reduced proliferation and increased apoptosis but does not affect terminal erythroid differentiation in a cell line model of Diamond‐Blackfan anemia. Stem Cells 26 (2): 323–329.

Moniz H, Gastou M, Leblanc T, et al. (2012) Primary hematopoietic cells from DBA patients with mutations in RPL11 and RPS19 genes exhibit distinct erythroid phenotype in vitro. Cell Death & Disease 3: e356.

Morgado‐Palacin L, Varetti G, Llanos S, et al. (2015) Partial loss of Rpl11 in adult mice recapitulates Diamond‐Blackfan anemia and promotes lymphomagenesis. Cell Reports 13 (4): 712–722.

Mukhopadhyay R, Jia J, Arif A, et al. (2009) The GAIT system: a gatekeeper of inflammatory gene expression. Trends in Biochemical Sciences 34 (7): 324–331.

Parrella S, Aspesi A, Quarello P, et al. (2014) Loss of GATA‐1 full length as a cause of Diamond‐Blackfan anemia phenotype. Pediatric Blood & Cancer 61 (7): 1319–1321.

Payne EM, Virgilio M, Narla A, et al. (2012) L‐Leucine improves the anemia and developmental defects associated with Diamond‐Blackfan anemia and del(5q) MDS by activating the mTOR pathway. Blood 120 (11): 2214–2224.

Pellagatti A, Hellstrom‐Lindberg E, Giagounidis A, et al. (2008) Haploinsufficiency of RPS14 in 5q‐ syndrome is associated with deregulation of ribosomal‐ and translation‐related genes. British Journal of Haematology 142 (1): 57–64.

Pereboom TC, Bondt A, Pallaki P, et al. (2014) Translation of branched‐chain aminotransferase‐1 transcripts is impaired in cells haploinsufficient for ribosomal protein genes. Experimental Hematology 42 (5): 394–403.e394.

Pfeifer CD, Schoennagel BP, Grosse R, et al. (2015) Pancreatic iron and fat assessment by MRI‐R2* in patients with iron overload diseases. Journal of Magnetic Resonance Imaging 42 (1): 196–203.

Quarello P, Garelli E, Carando A, et al. (2010) Diamond‐Blackfan anemia: genotype‐phenotype correlations in Italian patients with RPL5 and RPL11 mutations. Haematologica 95 (2): 206–213.

Quigley JG, Gazda H, Yang Z, et al. (2005) Investigation of a putative role for FLVCR, a cytoplasmic heme exporter, in Diamond‐Blackfan anemia. Blood Cells, Molecules & Diseases 35 (2): 189–192.

Rey MA, Duffy SP, Brown JK, et al. (2008) Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis. Haematologica 93: 1617–1626.

Sankaran VG, Ghazvinian R, Do R, et al. (2012) Exome sequencing identifies GATA1 mutations resulting in Diamond‐Blackfan anemia. Journal of Clinical Investigation 122 (7): 2439–2443.

Schutz S, Fischer U, Altvater M, et al. (2014) A RanGTP‐independent mechanism allows ribosomal protein nuclear import for ribosome assembly. eLife 3: e03473.

Tourlakis ME, Zhang S, Ball HL, et al. (2015) In vivo senescence in the Sbds‐deficient murine pancreas: cell‐type specific consequences of translation insufficiency. PLoS Genetics 11 (6): e1005288.

Varricchio L, Godbold J, Scott SA, et al. (2011) Increased frequency of the glucocorticoid receptor A3669G (rs6198) polymorphism in patients with Diamond‐Blackfan anemia. Blood 118 (2): 473–474.

Vlachos A and Muir E (2010) How I treat Diamond‐Blackfan anemia. Blood 116 (19): 3715–3723.

Vlachos A, Farrar JE, Atsidaftos E, et al. (2013) Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q‐ syndrome. Blood 122 (14): 2487–2490.

Yadav GV, Chakraborty A, Uechi T, et al. (2014) Ribosomal protein deficiency causes Tp53‐independent erythropoiesis failure in zebrafish. International Journal of Biochemistry and Cell Biology 49: 1–7.

Zheng J, Lang Y, Zhang Q, et al. (2015) Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation. Genes and Development 29 (14): 1524–1534.

Further Reading

Agmon I, Bashan A, Zarivach R, et al. (2005) Symmetry at the active site of the ribosome: structural and functional implications. Biological Chemistry 386 (9): 833–844.

Angrisani A, Vicidomini R, Turano M, et al. (2014) Human dyskerin: beyond telomeres. Biological Chemistry 395 (6): 593–610.

Choesmel V, Fribourg S, Aguissa‐Toure AH, et al. (2008) Mutation of ribosomal protein RPS24 in Diamond‐Blackfan anemia results in a ribosome biogenesis disorder. Human Molecular Genetics 17 (9): 1253–1263.

Dror Y, Donadieu J, Koglmeier J, et al. (2011) Draft consensus guidelines for diagnosis and treatment of Shwachman‐Diamond syndrome. Annals of the New York Academy of Sciences 1242: 40–55.

In K, Zaini MA, Muller C, et al. (2016) Shwachman‐Bodian‐Diamond syndrome (SBDS) protein deficiency impairs translation re‐initiation from C/EBPalpha and C/EBPbeta mRNAs. Nucleic Acids Research 44 (9): 4134–4146.

Kadakia S, Helman SN, Badhey AK, et al. (2014) Treacher Collins Syndrome: the genetics of a craniofacial disease. International Journal of Pediatric Otorhinolaryngology 78 (6): 893–898.

Robledo S, Idol RA, Crimmins DL, et al. (2008) The role of human ribosomal proteins in the maturation of rRNA and ribosome production. RNA 14 (9): 1918–1929.

Ross AP and Zarbalis KS (2014) The emerging roles of ribosome biogenesis in craniofacial development. Frontiers in Physiology 5: 26.

Ruggero D and Shimamura A (2014) Marrow failure: a window into ribosome biology. Blood 124 (18): 2784–2792.

Schmeing TM and Ramakrishnan V (2009) What recent ribosome structures have revealed about the mechanism of translation. Nature 461 (7268): 1234–1242.

Steitz TA (2008) A structural understanding of the dynamic ribosome machine. Nature Reviews Molecular Cell Biology 9 (3): 242–253.

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Paolini, Nahuel A, MacInnes, Alyson W, and von Lindern, Marieke(Aug 2016) Diamond–Blackfan Anaemia: From Genotype to Phenotype. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024471]