D iamond– B lackfan 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.

Danazol: An Effective and Underutilised Treatment Option in Diamond-Blackfan Anaemia

“…Over 50% of DBA cases have somatic mutations or deletions in one of 14 genes encoding for ribosomal proteins, with the RPS19 gene being the commonest genetic abnormality accounting for a quarter of cases [4, 7–9]. Genotype-phenotype correlations have been observed with RPL5 and RPL11 mutations associated with higher rates of physical malformations [8]. The exact molecular mechanism by which ribosomal dysfunction leads to ineffective erythropoiesis and red cell aplasia remains unclear.…”

RNA Binding Proteins and Regulation of mRNA Translation in Erythropoiesis

“…For instance, GATA-1 (GATA-binding factor 1) functions as one of the master regulators of erythropoiesis, inducing for instance (i) the expression of the Epo receptor (EpoR), (ii) commitment to the erythroid lineage, and (iii) transcription of the β-globin locus ( Gregory et al, 1999 ; Ferreira et al, 2005 ; Kim and Bresnick, 2007 ; Ribeil et al, 2013 ). GATA1 protein synthesis is reduced in Diamond-Blackfan anemia (DBA), a congenital red cell aplasia caused by reduced biosynthesis of ribosomes, and mutations in GATA1 can cause a DBA-like phenotype ( Ludwig et al, 2014 ; Vlachos et al, 2014 ; Paolini et al, 2016 ). Also of importance, particularly during terminal erythroid differentiation, is KLF1 (Kruppel-like factor 1, or E-KLF: erythroid KLF), a transcription factor involved in many cellular changes required for the maturation of erythroblasts to erythrocytes, including expression of β-globin ( Dzierzak and Philipsen, 2013 ; Perkins et al, 2016 ).…”

Csde1 binds transcripts involved in protein homeostasis and controls their expression in erythropoiesis

“…Defects in ribosomal proteins that are involved in ribosome biosynthesis cause Diamond Blackfan Anemia (DBA), a severe congenital anemia 2 . Interestingly, mutations in the erythroid transcription factor Gata1 also cause a DBA-like anemia 3,4 , which suggests that at least a part of the Gata1 target genes form a RNA regulon that is very sensitive to reduced ribosome availability 5 . Reduced expression of DBA-related ribosomal proteins in erythroblasts impairs translation of IRES (internal ribosomal entry site) containing transcripts 6 .…”