Diamond–Blackfan Anaemia: From Genotype to Phenotype


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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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]