A 28-year-old woman with Diamond-Blackfan anemia (DBA) is found to have a heterozygous pathogenic variant in RPS19. She develops a macrocytic anemia with pure red cell aplasia, elevated MCV, and elevated erythrocyte adenosine deaminase (eADA). The molecular mechanism linking ribosomal protein haploinsufficiency to erythroid failure is:

• A RPS19 haploinsufficiency causes decreased global protein synthesis affecting all hematopoietic lineages equally, with random predominance of erythroid failure
• B Loss of ribosomal protein triggers unfolded protein response (UPR) causing selective IRE1-alpha-mediated erythroid progenitor apoptosis
• C Ribosomal protein haploinsufficiency activates p53 via free ribosomal proteins (RPL5, RPL11) binding MDM2, stabilizing p53 to promote apoptosis of erythroid progenitors which are uniquely sensitive to p53-mediated cell death ✓
• D RPS19 haploinsufficiency specifically impairs GATA1 mRNA translation, reducing GATA1 protein levels below the threshold required for erythroid differentiation

Explanation

Diamond-Blackfan anemia (DBA) is caused by heterozygous loss-of-function mutations in ribosomal protein genes (most commonly RPS19, ~25% of cases; also RPL5, RPL11, RPS26, etc.). Ribosomal protein haploinsufficiency impairs ribosome biogenesis, causing free unassembled ribosomal proteins to accumulate. Free RPL5 and RPL11 bind and inhibit MDM2 (an E3 ubiquitin ligase that normally ubiquitinates p53 for proteasomal degradation), thereby stabilizing and activating p53. Erythroid progenitors (specifically BFU-E and CFU-E) are exquisitely sensitive to p53-driven apoptosis because of high endogenous p53 pathway activity during erythropoiesis. This p53-centric mechanism explains selective erythroid failure; elevated eADA is a specific biomarker. GATA1 mRNA translation impairment occurs in some DBA patients but is not the primary p53-pathway mechanism.

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

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Written and medically reviewed by the StethoPrep medical team.