Elsevier

Seminars in Hematology

Volume 48, Issue 2, April 2011, Pages 124-135
Seminars in Hematology

Untangling the Phenotypic Heterogeneity of Diamond Blackfan Anemia

https://doi.org/10.1053/j.seminhematol.2011.02.003Get rights and content

Diamond Blackfan anemia (DBA) is a lineage-selective inherited bone marrow failure syndrome characterized primarily by anemia and physical malformations. Recent advances in identifying the genetic abnormalities underlying DBA have demonstrated involvement of genes encoding both large (RPL) and small (RPS) ribosomal subunit proteins, including mutations of RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26 in 50% to 60% of affected patients. Despite significant progress, identification of gene abnormalities in the remaining patients remains an important question since present data suggest that mutations in other members of the ribosomal protein gene complement do not explain those cases without an identified genetic lesion in these genes. Genetic studies have also raised new questions with the recognition of substantial variability in the manifestations of DBA, ranging from ribosomal protein mutations in otherwise asymptomatic individuals to those with classic severe red blood cell aplasia with characteristic malformations, at times within the same kindred. In this review, we summarize the genetic basis of DBA and discuss mechanisms by which the phenotype of DBA might be modified.

Section snippets

Tugging the String: Gene Discovery in DBA

The first significant breakthrough in defining the genetic basis for DBA developed from the identification of a child with a t(X;19) balanced reciprocal translocation.1 This finding was followed by polymorphic marker linkage studies localizing a critical region in 29 multiplex families (ie, families with multiple affected members) to 19q13 and defining a critical region based on three probands with microdeletions involving 19q13.2.2, 3 A ribosomal protein (r-protein) gene, RPS19, was

Confronting the Knots: New Insights and New Problems in Genotype–Phenotype Correlations

One of the most confounding problems in DBA research has been the lack of clear correlation between genotype and phenotype. This may be partly explained by the relatively small numbers of mutations in r-protein genes other than RPS19, as well as a relatively large fraction of unknown mutations. However, with the advent of RPS19 testing, it became clear that no distinctive clinical phenotype could reliably differentiate RPS19-mutated from non–RPS19-mutated DBA.6, 13, 49 Even more surprising was

Elucidating the Genotype/Phenotype Connection in DBA: Next Steps

It is increasingly apparent that assembling and exporting a functional ribosome is a complex and interactive process involving myriad interactions. The process does not occur in isolation, with studies demonstrating converging and diverging signaling at the level of ribosome assembly in such diverse cellular processes as nutrient availability, cell cycle control, cell size control, and apoptosis.58, 59, 60, 61, 62 In addition to the four mature rRNAs and approximately 80 structural ribosomal

Conclusion

The genetic landscape of DBA has changed dramatically in the past 12 years. From having no available genetic testing for DBA, more than half of DBA patients are now classifiable with a specific mutation in one of nine different genes. Mutational analysis for many of these genes, initially limited to research studies, are becoming available for routine testing on a clinical basis. As a result of these observations, investigators are exploring the mechanistic connections between erythroid

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    Supported by grants from the National Institutes of Health (K08 HL092224 and 5R01-HL079567-04), the Passano Foundation, the Swedish Research Council, and the Daniella Maria Arturi Foundation.

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