What’s in a name?
Mitchell J. Weiss, Philip J. Mason, Monica Bessler
Mitchell J. Weiss, Philip J. Mason, Monica Bessler
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Commentary

What’s in a name?

Abstract

Mutations in numerous genes encoding ribosomal proteins (RPs) occur in 50%–70% of individuals with Diamond-Blackfan anemia (DBA), establishing the disease as a ribosomopathy. As described in this issue of JCI, Sankaran, Gazda, and colleagues used genome-wide exome sequencing to study DBA patients with no detectable mutations in RP genes. They identified two unrelated pedigrees in which the disease is associated with mutations in GATA1, which encodes an essential hematopoietic transcription factor with no known mechanistic links to ribosomes. These findings ignite an interesting and potentially emotional debate on how we define DBA and whether the term should be restricted to pure ribosomopathies. More generally, the work reflects the powerful knowledge and controversies arising from the deluge of data generated by new genetic technologies that are being used to analyze human diseases.

Authors

Mitchell J. Weiss, Philip J. Mason, Monica Bessler

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Figure 1

Current model for how RP haploinsufficiency causes DBA.

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Current model for how RP haploinsufficiency causes DBA. (A) Normal eryth...
(A) Normal erythroblasts produce large numbers of ribosomes for protein synthesis. Levels of p53 remain low via a feedback loop whereby MDM2, a transcriptional p53 target, ubiquitinates p53 to promote its degradation by proteasomes. (B) Haploinsufficiency for specific RPs causes accumulation of other RPs, which bind to MDM2, thereby inhibiting its ability to promote p53 degradation. Consequently, p53 accumulates and triggers cell cycle arrest and apoptosis.