Genetics of the Ribosomopathies

Abstract

Ribosomopathies refer collectively to a group of disorders characterised by disruption of ribosome synthesis. Classically, these are rare genetic syndromes with developmental abnormalities, often involving abnormal blood cell production, as seen in Diamond Blackfan anaemia, the 5q‐myelodysplastic syndrome and Shwachman‐Diamond syndrome or causing craniofacial anomalies (Treacher Collins syndrome). However, research has recognised several new putative ribosomopathies (Bowen‐Conradi syndrome and North American Indian childhood cirrhosis), and new revelations may force the reclassification of some older disorders (dyskeratosis congenita and cartilage hair hypoplasia). Finally, some, but not all, ribosomopathies predispose patients to solid tumours or haematologic malignancies. Here, we critically review the underlying genetics in old and new ribosomopathies and examine the pathophysiologic consequences of aberrant ribosome biogenesis.

Key Concepts:

  • Ribosomopathies refer collectively to a group of disorders characterised by disruption of ribosome synthesis.

  • Most ribosomopathies are rare genetic syndromes with developmental abnormalities, often involving abnormal blood cell production or causing craniofacial anomalies.

  • There are several new putative ribosomopathies and the classification of some disorders is in flux.

  • Diamond‐Blackfan anemia and Treacher Collins syndrome are two well‐described ribosomopathies that share pathophysiologic similarities but have different clinical manifestations for the most part.

  • Some, but not all, ribosomopathies predispose patients to solid tumours or haematologic malignancies.

Keywords: ribosomopathies; developmental disorders; ribosomal stress; p53; bone marrow failure syndromes

Figure 1.

Ribosomopathies and model of pre‐rRNA processing. Ribosomopathies are noted in green (established), red (disputed) and blue (putative), depending on the degree of confidence in their role in ribosome synthesis.

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References

Armistead J, Khatkar S, Meyer B et al. (2009) Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen‐Conradi syndrome. American Journal of Human Genetics 84: 728–739.

Barna M, Pusic A, Zollo O et al. (2008) Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456: 971–975.

Boocock GR, Morrison JA, Popovic M et al. (2003) Mutations in SBDS are associated with Shwachman‐Diamond syndrome. Nature Genetics 33: 97–101.

Buchhaupt M, Meyer B, Kotter P and Entian KD (2006) Genetic evidence for 18S rRNA binding and an Rps19p assembly function of yeast nucleolar protein Nep1p. Molecular Genetics and Genomics 276: 273–284.

Chagnon P, Michaud J, Mitchell G et al. (2002) A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis. American Journal of Human Genetics 71: 1443–1449.

Choesmel V, Bacqueville D, Rouquette J et al. (2007) Impaired ribosome biogenesis in Diamond‐Blackfan anemia. Blood 109: 1275–1283.

Dai MS and Lu H (2004) Inhibition of MDM2‐mediated p53 ubiquitination and degradation by ribosomal protein L5. Journal of Biological Chemistry 279: 44475–44482.

Danilova N, Sakamoto KM and Lin S (2008) Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family. Blood 112: 5228–5237.

Dauwerse JG, Dixon J, Seland S et al. (2011) Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nature Genetics 43: 20–22.

De Benedetti A and Graff JR (2004) eIF‐4E expression and its role in malignancies and metastases. Oncogene 23: 3189–3199.

De Souza RA (2010) Mystery behind Bowen‐Conradi syndrome solved: a novel ribosome biogenesis defect. Clinical Genetics 77: 116–118.

Dixon J, Jones NC, Sandell LL et al. (2006) Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities. Proceedings of the National Academy of Sciences of the USA 103: 13403–13408.

Doherty L, Sheen MR, Vlachos A et al. (2010) Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond‐Blackfan anemia. American Journal of Human Genetics 86: 222–228.

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

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

Farrar JE, Nater M, Caywood E et al. (2008) Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond‐Blackfan anemia. Blood 112: 1582–1592.

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: 917–929.

Flygare J, Aspesi A, Bailey JC et al. (2007) Human RPS19, the gene mutated in Diamond‐Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Blood 109: 980–986.

Freed EF and Baserga SJ (2010) The C‐terminus of Utp4, mutated in childhood cirrhosis, is essential for ribosome biogenesis. Nucleic Acids Research 38: 4798–4806.

Freed EF, Prieto JL, McCann KL, McStay B and Baserga SJ (2012) NOL11, implicated in the pathogenesis of North American Indian childhood cirrhosis, is required for pre‐rRNA transcription and processing. PLoS Genetics 8: e1002892.

Gazda HT, Grabowska A, Merida‐Long LB et al. (2006) Ribosomal protein S24 gene is mutated in Diamond‐Blackfan anemia. American Journal of Human Genetics 79: 1110–1118.

Gazda HT, Preti M, Sheen MR et al. (2012) Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre‐ribosomal RNA processing defect in diamond‐blackfan anemia. Human Mutation 33: 1037–1044.

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: 769–780.

Gonzales B, Henning D, So RB et al. (2005) The Treacher Collins syndrome (TCOF1) gene product is involved in pre‐rRNA methylation. Human Molecular Genetics 14: 2035–2043.

Gripp KW, McDonald‐McGinn DM, La Rossa D et al. (2001) Bilateral microtia and cleft palate in cousins with Diamond‐Blackfan anemia. American Journal of Medical Genetics 101: 268–274.

Horn HF and Vousden KH (2008) Cooperation between the ribosomal proteins L5 and L11 in the p53 pathway. Oncogene 27: 5774–5784.

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: 262–272.

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

Liu JM and Ellis SR (2006) Ribosomes and marrow failure: coincidental association or molecular paradigm? Blood 107: 4583–4588.

Lo KY, Li Z, Bussiere C et al. (2010) Defining the pathway of cytoplasmic maturation of the 60S ribosomal subunit. Molecular Cell 39: 196–208.

MacInnes AW, Amsterdam A, Whittaker CA, Hopkins N and Lees JA (2008) Loss of p53 synthesis in zebrafish tumors with ribosomal protein gene mutations. Proceedings of the National Academy of Sciences of the USA 105: 10408–10413.

McGowan KA, Li JZ, Park CY et al. (2008) Ribosomal mutations cause p53‐mediated dark skin and pleiotropic effects. Nature Genetics 40: 963–970.

Meier UT (2006) How a single protein complex accommodates many different H/ACA RNAs. Trends in Biochemical Sciences 31: 311–315.

Menne TF, Goyenechea B, Sanchez‐Puig N et al. (2007) The Shwachman‐Bodian‐Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genetics 39: 486–495.

Meyer B, Wurm JP, Kotter P et al. (2011) The Bowen‐Conradi syndrome protein Nep1 (Emg1) has a dual role in eukaryotic ribosome biogenesis, as an essential assembly factor and in the methylation of Psi1191 in yeast 18S rRNA. Nucleic Acids Research 39: 1526–1537.

O'Donohue MF, Choesmel V, Faubladier M, Fichant G and Gleizes PE (2010) Functional dichotomy of ribosomal proteins during the synthesis of mammalian 40S ribosomal subunits. Journal of Cell Biology 190: 853–866.

Pittman RH, Andrews MT and Setzer DR (1999) A feedback loop coupling 5 S rRNA synthesis to accumulation of a ribosomal protein. Journal of Biological Chemistry 274: 33198–33201.

Ridanpaa M, van Eenennaam H, Pelin K et al. (2001) Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage‐hair hypoplasia. Cell 104: 195–203.

Saitsu H, Osaka H, Sasaki M et al. (2011) Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal‐recessive hypomyelinating leukoencephalopathy. American Journal of Human Genetics 89: 644–651.

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

Sasaki M, Kawahara K, Nishio M et al. (2011) Regulation of the MDM2‐P53 pathway and tumor growth by PICT1 via nucleolar RPL11. Nature Medicine 17: 944–951.

Schmitt ME and Clayton DA (1993) Nuclear RNase MRP is required for correct processing of pre‐5.8S rRNA in Saccharomyces cerevisiae. Molecular and Cellular Biology 13: 7935–7941.

Singh SA, Vlachos A, Morgenstern NJ et al. (2012) Breast cancer in a case of Shwachman Diamond syndrome. Pediatric Blood and Cancer 59: 945–946.

Thiel CT, Horn D, Zabel B et al. (2005) Severely incapacitating mutations in patients with extreme short stature identify RNA‐processing endoribonuclease RMRP as an essential cell growth regulator. American Journal of Human Genetics 77: 795–806.

Valdez BC, Henning D, So RB, Dixon J and Dixon MJ (2004) The Treacher Collins syndrome (TCOF1) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor. Proceedings of the National Academy of Sciences of the USA 101: 10709–10714.

Vlachos A, Rosenberg PS, Atsidaftos E, Alter BP and Lipton JM (2012) Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan anemia registry. Blood 119: 3815–3819.

Watkins NJ and Bohnsack MT (2012) The box C/D and H/ACA snoRNPs: key players in the modification, processing and the dynamic folding of ribosomal RNA. Wiley Interdisciplinary Reviews: RNA 3: 397–414.

Wong CC, Traynor D, Basse N, Kay RR and Warren AJ (2011) Defective ribosome assembly in Shwachman‐Diamond syndrome. Blood 118: 4305–4312.

Yoon A, Peng G, Brandenburger Y et al. (2006) Impaired control of IRES‐mediated translation in X‐linked dyskeratosis congenita. Science 312: 902–906.

Yu B, Mitchell GA and Richter A (2005) Nucleolar localization of cirhin, the protein mutated in North American Indian childhood cirrhosis. Experimental Cell Research 311: 218–228.

Further Reading

Goldberg TA, Singh S, Solaimanzadeh J et al. (2011) Knockdown of p53 improves hematopoietic and erythroid differentiation defects in mouse embryonic stem cell models of Diamond Blackfan anemia. Blood 118: 330.

Held WA, Ballou B, Mizushima S and Nomura M (1974) Assembly mapping of 30 S ribosomal proteins from E. coli. Further studies. Journal of Biological Chemistry 249: 3103–3111.

Mason PJ and Bessler M (2011) The genetics of dyskeratosis congenita. Cancer Genetics 204: 635–645.

Shenoy N, Kessel R, Bhagat TD et al. (2012) Alterations in the ribosomal machinery in cancer and hematologic disorders. Journal of Hematology and Oncology 5: 32.

Shimamura A and Alter BP (2010) Pathophysiology and management of inherited bone marrow failure syndromes. Blood Reviews 24: 101–122.

Tschochner H and Hurt E (2003) Pre‐ribosomes on the road from the nucleolus to the cytoplasm. Trends in Cell Biology 13: 255–263.

Zemp I and Kutay U (2007) Nuclear export and cytoplasmic maturation of ribosomal subunits. FEBS Letters 581: 2783–2793.

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Liu, Johnson M, Lipton, Jeffrey M, and Ellis, Steven R(Feb 2013) Genetics of the Ribosomopathies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023863]