In Diamond-Blackfan anemia (DBA), which molecular mechanism underlies the selective failure of erythropoiesis?

• A Mutations in the GATA-1 transcription factor abrogate erythroid lineage commitment
• B Mutations in ribosomal protein genes cause ribosomal stress, stabilizing p53 via MDM2 sequestration, which triggers apoptosis selectively in erythroid progenitors due to their high ribosome demand during differentiation ✓
• C EPO receptor mutations prevent erythroid progenitor survival signalling
• D Autoantibodies against BFU-E and CFU-E progenitors destroy the erythroid compartment

Explanation

DBA is caused by heterozygous mutations in ribosomal protein genes (most commonly RPS19, also RPL5, RPS26, etc.). Haploinsufficiency of ribosomal proteins causes ribosomal stress, which sequesters MDM2 away from p53, stabilizing p53 and triggering apoptosis. Erythroid progenitors are exquisitely sensitive because they require extremely high ribosome output during differentiation (hemoglobin synthesis demands massive translational activity). GATA-1 mutations can cause DBA-like phenotype rarely, but is not the primary mechanism of classic DBA. EPO receptor mutations cause secondary erythrocytosis, not aplasia. DBA is not autoimmune-mediated.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.