A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia

• Published in: Blood Vol. 116; no. 15; pp. 2826 - 2835
• Main Authors: Devlin, Emily E., DaCosta, Lydie, Mohandas, Narla, Elliott, Gene, Bodine, David M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 14.10.2010; Americain Society of Hematology; American Society of Hematology
• Series: Red Cells, Iron, and Erythropoiesis
• Subjects: Anemia, Diamond-Blackfan - blood; Anemia, Diamond-Blackfan - genetics; Anemia, Diamond-Blackfan - pathology; Anemias. Hemoglobinopathies; Animals; Base Sequence; Biological and medical sciences; Disease Models, Animal; Diseases of red blood cells; DNA Primers - genetics; Erythroid Precursor Cells - pathology; Erythropoiesis - genetics; Female; Gene Expression Profiling; Hematologic and hematopoietic diseases; Humans; Male; Medical sciences; Mice; Mice, Transgenic; Mutation, Missense; Point Mutation; Pregnancy; Red Cells, Iron, and Erythropoiesis; Ribosomal Proteins - genetics; RNA, Messenger - genetics; Blackfan-Diamond disease; Animal model; Hematology; Ribosomal protein S19; Rodentia; Transgenic animal; Hemopathy; Congenital disease; Vertebrata; Mammalia; Gene; Mouse; Point mutation; Recessive character; Genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-03-275776

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.