Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with 
mutations in at least 8 different ribosomal protein genes. Mutations in the gene 
encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% 
of DBA families. Most of these mutations disrupt either the translation or 
stability of the RPS19 protein and are predicted to cause DBA by 
haploinsufficiency. However, approximately 30% of RPS19 mutations are missense 
mutations that do not alter the stability of the RPS19 protein and are 
hypothesized to act by a dominant negative mechanism. To formally test this 
hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation 
in which an arginine residue is replaced with a tryptophan residue at codon 62 
(RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. 
Conditional expression of RPS19R62W resulted in growth retardation, a mild 
anemia with reduced numbers of erythroid progenitors, and significant inhibition 
of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated 
more than 700 dysregulated genes belonging to the same pathways that are 
disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a 
dominant negative DBA mutation.