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.

Figure 1. Current model for how RP haploinsufficiency causes DBA.

(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.

Figure 2. GATA1 mutations associated with human disease.

The diagram indicates GATA-1 protein with functional modules including the NH₂-terminal activation domain (NAD), amino zinc finger (Nf), and carboxyl zinc finger (Cf). The NAD physically interacts with the retinoblastoma protein (Rb), which may modulate the ability of GATA-1 to regulate cell division and/or survival. Loss of the NAD through somatically acquired splice, frameshift, or nonsense mutations causes myeloproliferative disorder and leukemia in young children with Down syndrome (trisomy 21). In the absence of Down syndrome, germline mutations resulting in loss of the NAD are associated with congenital anemia. Different surfaces of the Nf interact with DNA (nor shown) and protein cofactors including FOG1 and SCL/TAL1. Missense mutations that alter these interaction surfaces of the Nf cause inherited anemia and/or thrombocytopenia with other abnormalities, as indicated.

Figure 3. Shared and distinct phenotypes in congenital red cell aplasia caused by mutations in RP genes and in GATA1.

eADA, erythrocyte adenosine deaminase activity, MCV, mean corpuscular volume; Hb, hemoglobin; TMD, transient myeloproliferative disorder.