Untangling the Phenotypic Heterogeneity of Diamond Blackfan Anemia
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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Cited by (40)
Loss of coordinated expression between ribosomal and mitochondrial genes revealed by comprehensive characterization of a large family with a rare Mendelian disorder
2021, GenomicsCitation Excerpt :The nature of the causative genetic mutation, epistastic interactions, and environmental factors can accentuate, mitigate, or sometimes completely mask a potentially pathogenic genetic variant. Diamond Blackfan Anemia (DBA) is an example of a monoallelic, genetic disease exhibiting incomplete penetrance and variable expressivity (reviewed in [1]). DBA can lead to developmental and hematological defects that often manifest in the first year of infancy and is caused by haploinsufficiency in the protein synthesis machinery due to loss of function or missense mutations.
Ribosomopathies-A tree of pathologies with many roots and branches!
2021, Emerging Concepts in Ribosome Structure, Biogenesis, and FunctionCzech and Slovak Diamond-Blackfan Anemia (DBA) Registry update: Clinical data and novel causative genetic lesions
2020, Blood Cells, Molecules, and DiseasesCitation Excerpt :The detection rate of mutations involving RP genes in the Czech DBA Registry was high compared to published data. Distribution of the respective genomic lesions with predominance of RPS19 point mutations is in accordance with previous observations of ours and other groups [3–5,20,36,37]. The incidence of familial DBA in our cohort was relatively low (15%) considering that some of the pedigrees were asymptomatic and revealed by familial screening (ID 2022, 2194, 2195).
Maternal Ribosomes Are Sufficient for Tissue Diversification during Embryonic Development in C. elegans
2019, Developmental CellCitation Excerpt :These disorders result from haploinsufficiency of ribosomal components or ribosome maturation factors, but penetrance even among genetic heterozygotes is variable or incomplete. Healthy family members can carry the same mutation (e.g., 43% silent carriers [Moetter et al., 2011]) as patients, and certain tissues are affected more than others (shared phenotype of bone marrow failure in the case of DBA) (Carlston et al., 2017; Ellis and Lipton, 2008; Farrar and Dahl, 2011). C. elegans may provide a paradigm and model for studying genetic influences, checkpoint control, and other modulating factors in ribosomopathy.
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.